Compounds as L-cystine crystallization inhibitors and uses thereof

ABSTRACT

A method of preventing or inhibiting L-cystine crystallization is disclosed, using the compounds of formula I:
 
R 1a —[O] v -(-A-L-) m -A-[O] v —R 1b    I
 
wherein A, L, R 1a , R 1b , m, and v are as described herein. The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of conditions that are causally related to L-cystine crystallization, such as comprising (but not limited to) kidney stones.

RELATED APPLICATIONS

The present application is a Division of co-pending non-provisionalapplication Ser. No. 14/569,737, filed Dec. 14, 2014, which in turn, isa Division of non-provisional application Ser. No. 13/491,816, filedJun. 8, 2012, now U.S. Pat. No. 8,916,609, issued Dec. 23, 2014, whichin turn, claims the benefit under 35 U.S.C. § 119 of U.S. ProvisionalApplication Ser. No. 61/495,585. filed Jun. 10, 2011. All of saidapplications are hereby incorporated herein by reference in theirentireties.

FIELD OF THE INVENTION

The present invention relates to the identification of compounds thatinhibit L-cystine crystallization, and the use of such compounds andcompositions thereof to prevent or slow L-cystine crystal production.This invention also relates to methods for preventing and/or treatingconditions that are causally related to L-cystine crystallization, suchas comprising (but not limited to) kidney stones, using the compounds ofthe invention. It is to be understood that such compounds may be usedeither alone or in combination with other compounds having the activityset forth herein.

BACKGROUND OF THE INVENTION

L-cystine stones account for less than 2% of adult kidney stones andaffect more than 100,000 U.S. patients. L-cystine stones, which arelarger and are more likely to cause chronic kidney disease than calciumoxalate monohydrate (COM) stones, form as a consequence of excessivelevels of L-cystine in the urine due to defective reabsorption offiltered cystine [1]. This autosomal recessive disorder is caused bymutations in one of two genes coding for components of proximal renaltubule amino acid transporters. Affected genes are either SLC3A1 onchromosome 2 leading to type A cystinuria, or SLC7A9 on chromosome 19leading to type B [2]. The low solubility of L-cystine [3] induces rapidcrystallization, which is followed by aggregation to generate stones(FIG. 1A) with sizes that can achieve centimeter dimensions.

Current treatments include high fluid intake [4], increasing urine pHthrough ingestion of alkalinizing potassium or sodium salts [4, 5], orthe administration of L-cystine binding thiol drugs (CBTDs), such asD-penicillamine (HS—C(CH₃)₂—CH(NH₂)—COOH) and α-mercaptopropionylglycine(α-MPG or tiopronin: HS—CHCH₃—CO—NH—CH₂—COOH), which undergo athiol-disulfide exchange with L-cystine to generate more solubleproducts [1]. These treatments suppress, but often do not completelyprevent, stone formation. Thiol drugs have an unpleasant odor and cancause adverse side-effects, such as nausea, fever, fatigue, and skinallergies [5]. CBTDs are accompanied by high fluid intake to achieve acystine excretion rate of 2.9 mM/day (i.e. urine volumes of 3 L/day) [4]and thiol excretion rates of 0.5-6 mM/day. A shortcoming of thiol drugs,however, is their inadequacy to reduce and solubilize large enoughquantities of L-cystine in the urine based on acceptable dosages (up to2000 mg/day), which are limited due to hypersensitivity and toxicityconcerns.

Therefore, there is a need for an improved method to prevent, inhibit orslow L-cystine crystal production, and it is toward the fulfillment ofthat need that the present invention is directed.

SUMMARY OF THE INVENTION

In a first aspect, the present invention relates to the prevention ofL-cystine kidney stones based on crystal growth inhibition via thebinding of tailored growth inhibitors to specific crystal surfacesthrough molecular recognition.

Thus, one aspect of the invention provides a method for preventing,inhibiting or slowing the growth of L-cystine crystallization comprisingadministering an effective amount of a compound of formula I:R^(1a)—[O]_(v)-(-A-L-)_(m)-A-[O]_(v)—R^(1b)   I

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof; andwherein

each A is independently

each X and Y is independently S, S(O), S(O)₂, or C(R⁵)q;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(3c), R^(3d), R^(4a), R^(4b), andR⁵ is independently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,and substituted or unsubstituted cycloalkyl; the subscript q is 1 or 2;the dotted bond is a single or a double bond;provided that when one of X and Y is S, S(O), or S(O)₂, then the dottedbond is a single bond;

L is —O—C₁-C₆ alkylene-O—, —O-aryl-O—, or a group —O—(CH₂—CH₂—O—)_(t)—;the subscript t is 1-10; the subscript m is 0-10; and

each R^(1a) and R^(1b) is independently selected from substituted orunsubstituted alkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl, and substituted or unsubstituted cycloalkyl; andeach subscript v is 0 or 1;

In one particular embodiment, with respect to formula I, when A is Ia′,both X and Y are S, S(O), or S(O)₂, and m is 0, then each subscript v is0.

In one embodiment, with respect to formula I, A is

and wherein R^(2a), R^(2b), R^(3a), R^(3b), R^(3c), R^(3d), R^(4a),R^(4b), and R⁵ are as described for formula I.

In one embodiment, with respect to formula I, subscript m is 1-5.

In one embodiment, with respect to formula I, L is —O—CH₂—O—. In anotherembodiment L is —O—CH₂—CH₂—O—.

In one embodiment, with respect to formula I, L is

In one embodiment, with respect to formula I, L is —O—(CH₂—CH₂—O)_(t)—;and the subscript t is 1; In another embodiment the subscript t is 2.

In one embodiment, with respect to formula I, subscript m is 0.

In one embodiment, with respect to formula I, the subscript m is 0; andthe subscript v is 0.

In one embodiment, with respect to formula I, subscript m is 0; and thecompound is according to formula II:R^(1a)-A-R^(1b)   II;

and wherein A, R^(1a) and R^(1b) are as described for formula I.

Another aspect of the invention provides a method for preventinginhibiting, or slowing the growth of L-cystine crystallizationcomprising administering an effective amount of a compound of formulaeIIIa, IIIb, IIIc, IIId, or IIIe:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof; andwherein

each R^(1a) and R^(1b) is independently selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl, and substituted or unsubstituted cycloalkyl;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(3c), R^(3d), R^(4a), R^(4b) andR⁵ is independently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,and substituted or unsubstituted cycloalkyl; and the subscript v is 0,1, or 2.

In one particular embodiment of the invention, with respect to formula Iand IIIa-IIIe, each of each R^(2a), R^(2b), R^(3a), R^(3b), R^(3c),R^(3d), R^(4a), R^(4b) and R⁵ is H.

In another particular embodiment of the invention, with respect toformula I and IIIa-IIIe, each of R^(1a) and R^(1b) is Me. In yet anotherembodiment, one of R^(1a) and R^(1b) is Me and the other is H.

In yet another particular embodiment of the invention, with respect toformula I, each n1 and n2 is 0.

Another aspect of the invention provides a method for preventinginhibiting, or slowing the growth of L-cystine crystallizationcomprising administering an effective amount of a compound of formulaeXIIIa, XIIIb, XIIIc, or XIIId:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof

Another aspect of the invention provides a pharmaceutical compositionfor preventing, inhibiting, or slowing the growth of L-cystinecrystallization comprising a pharmaceutically acceptable carrier and apharmaceutically effective amount of a compound according to formula I.

Yet another aspect of the invention provides a method for preventing,inhibiting or slowing growth of L-cystine kidney-stone formation in asubject in need thereof, the method comprising administering to thesubject a pharmaceutically effective amount of a compound according toformula I.

Yet another aspect of the invention provides a method of treating asubject having chronic kidney disease, comprising administering to thesubject a pharmaceutically effective amount of a compound according toformula I.

A further aspect of the invention provides a method for reducing aL-cystine crystal concentration in a human or animal comprisingadministering to a human or animal a pharmaceutically effective amountof a compound according to formula I.

A further aspect of the invention provides a method for treating anL-cystine crystal-related condition in a human or animal, comprisingadministering to a human or animal a pharmaceutically effective amountof a compound according to formula I.

A further aspect of the invention provides a combination to treat orprevent an L-cystine crystal-related condition, consisting of a compoundaccording to formula I and another treatment or treatments, which mayinclude high fluid intake or alkalinizing potassium or sodium salts.

In one embodiment, with respect to the above methods, the L-cystinerelated condition is cystinuria.

In one embodiment, with respect to the above methods, the L-cystinerelated condition is kidney stone disease.

In a further aspect, the present invention provides pharmaceuticalcompositions, comprising a compound or compounds of the invention, and asuitable biocompatible or bioinert carrier, excipient or diluent. Inthis aspect of the invention, pharmaceutical composition can compriseone or more of the compounds described herein. Moreover, the compoundsof the present invention useful in pharmaceutical compositions andtreatment methods disclosed herein, are all pharmaceutically acceptableas prepared and used.

In a further aspect, the present invention provides compositionscomprising a combination of a compound of the invention with variouscompounds or agents that may have a like effect on L-cystinecrystallization. In this aspect of the invention, the pharmaceuticalcomposition can comprise one or more of the compounds described herein,individually or in combination with each other.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing detailed description, whichproceeds with reference to the following illustrative drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the hierarchical structure of L-cystine kidney stones,including the typical hexagonal platelet crystal habit formed in theabsence of growth inhibitors. (A) Human stones with millimeter-scaledimensions (courtesy of M. Lewis, International Cystinuria Foundation).(B) A hexagonal L-cystine crystal prepared in vitro. The faint lines onthe top surface of the crystal, parallel to the edges, are the {100}steps. (C) Two adjacent helices of L-cystine molecules, viewed on the(100) plane, each winding about a 6₁ screw axis that coincides with thec axis. Six L-cystine molecules, denoted C1 to C6, span the 5.6 nm caxis. Key intermolecular interactions include amine-carboxylate hydrogenbonds along the helix (I, d_(N . . . O)=2.87 Å) and S . . . Sinteractions (II, d_(S . . . S)=3.47 Å) between helices at intervals ofc/2, depicted here for C1 and C4 along the [010] direction (identical S. . . S interactions occur at symmetry-related sites along the otherfive equivalent directions). (D) Intermolecular amine-carboxylatehydrogen bonds in the (001) plane (III, d_(N . . . O)=2.79 Å; IV,d_(N . . . O)=2.81 Å). Atom color code: carbon (gray), oxygen (red),nitrogen (blue), sulfur (yellow), hydrogen (white). (E) Schematicillustration of a hexagonal L-cystine crystal, with Miller indices. Thesix planes flanking (001) belong to the {100} family.

FIG. 2 depicts atomic force microscopy images of L-cystine crystalsurface acquired in deflection mode.

(A,B) Real-time in situ AFM images of a L-cystine crystal, acquired 12minutes apart. A pair of hexagonal hillocks generated by two closelyspaced dislocations serve as landmarks. (C,D) AFM images of a singledislocation center of (C) L-cystine and (D) D-cystine crystal duringgrowth. (E,F) AFM image of a hexagonal growth hillock on the (001) faceof L-cystine before and after addition of an additive revealingroughening of the {100} steps due to step pinning. Images were acquiredin aqueous solutions containing 2 mM L-cystine.

FIG. 3 depicts comparison of inhibitory effect of different diesters ofL-Cystine (0.015 mM).

FIG. 4 depicts comparison of inhibitory effect of different additives.

FIG. 5 depicts comparison of inhibitory effect of different monoestersof L-Cystine (0.015 mM and 0.03 mM).

DETAILED DESCRIPTION OF THE INVENTION Definitions

When describing the compounds, pharmaceutical compositions containingsuch compounds and methods of using such compounds and compositions, thefollowing terms have the following meanings unless otherwise indicated.It should also be understood that any of the moieties defined forthbelow may be substituted with a variety of substituents, and that therespective definitions are intended to include such substituted moietieswithin their scope.

As used in this specification and the appended claims, the singularforms “a”, “an”, and “the” include plural references unless the contextclearly dictates otherwise. Thus for example, reference to “the method”includes one or more methods, and/or steps of the type described hereinand/or which will become apparent to those persons skilled in the artupon reading this disclosure.

“Acyl” refers to a group or radical —C(O)R²⁰, where R²⁰ is hydrogen,alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,heteroaryl, heteroarylalkyl as defined herein. Representative examplesinclude, but are not limited to, formyl, acetyl, cylcohexylcarbonyl,cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl and the like.

“Acylamino” refers to a group or radical —NR²¹C(O)R²², where R²¹ ishydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl,heteroalkyl, heteroaryl, heteroarylalkyl and R²² is hydrogen, alkyl,alkoxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl,heteroaryl or heteroarylalkyl, as defined herein. Representativeexamples include, but are not limited to, formylamino, acetylamino,cyclohexylcarbonylamino, cyclohexylmethyl-carbonylamino, benzoylamino,benzylcarbonylamino and the like.

“Acyloxy” refers to the group or radical —OC(O)R²³ where R²³ ishydrogen, alkyl, aryl or cycloalkyl.

“Substituted alkenyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkenyl group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkoxy” refers to the group —OR²⁴ where R²⁴ is alkyl. Particular alkoxygroups include, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy,1,2-dimethylbutoxy, and the like.

“Substituted alkoxy” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkoxy group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,heteroaryl, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy,thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— andaryl-S(O)₂—.

“Alkoxycarbonylamino” refers to the group —NR²⁵C(O)R²⁶ where R²⁵ ishydrogen, alkyl, aryl or cycloalkyl, and R²⁶ is alkyl or cycloalkyl.

“Alkyl” refers to monovalent saturated alkane radical groupsparticularly having up to about 11 carbon atoms, more particularly as alower alkyl, from 1 to 8 carbon atoms and still more particularly, from1 to 6 carbon atoms. The hydrocarbon chain may be eitherstraight-chained or branched. This term is exemplified by groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl,n-hexyl, n-octyl, tert-octyl and the like. The term “lower alkyl” refersto alkyl groups having 1 to 6 carbon atoms. The term “alkyl” alsoincludes “cycloalkyls” as defined below.

“Substituted alkyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkyl group having 1or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, heteroaryl, keto, nitro, thioalkoxy, substituted thioalkoxy,thioaryloxy, thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂—, andaryl-S(O)₂—.

“Alkylene” refers to divalent saturated alkene radical groups having 1to 11 carbon atoms and more particularly 1 to 6 carbon atoms which canbe straight-chained or branched. This term is exemplified by groups suchas methylene (—CH₂—), ethylene (—CH₂CH₂—), the propylene isomers (e.g.,—CH₂CH₂CH₂— and —CH(CH₃)CH₂—) and the like.

“Substituted alkylene” includes those groups recited in the definitionof “substituted” herein, and particularly refers to an alkylene grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, halogen, hydroxyl, keto, nitro, thioalkoxy,substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)—,aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkenyl” refers to monovalent olefinically unsaturated hydrocarbylgroups preferably having 2 to 11 carbon atoms, particularly, from 2 to 8carbon atoms, and more particularly, from 2 to 6 carbon atoms, which canbe straight-chained or branched and having at least 1 and particularlyfrom 1 to 2 sites of olefinic unsaturation. Particular alkenyl groupsinclude ethenyl (—CH═CH₂), n-propenyl (—CH₂CH═CH₂), isopropenyl(—C(CH₃)═CH₂), vinyl and substituted vinyl, and the like.

“Alkenylene” refers to divalent olefinically unsaturated hydrocarbylgroups particularly having up to about 11 carbon atoms and moreparticularly 2 to 6 carbon atoms which can be straight-chained orbranched and having at least 1 and particularly from 1 to 2 sites ofolefinic unsaturation. This term is exemplified by groups such asethenylene (—CH═CH—), the propenylene isomers (e.g., —CH═CHCH₂— and—C(CH₃)═CH— and —CH═C(CH₃)—) and the like.

“Alkynyl” refers to acetylenically or alkynically unsaturatedhydrocarbyl groups particularly having 2 to 11 carbon atoms and moreparticularly 2 to 6 carbon atoms which can be straight-chained orbranched and having at least 1 and particularly from 1 to 2 sites ofalkynyl unsaturation. Particular non-limiting examples of alkynyl groupsinclude acetylenic, ethynyl (—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Substituted alkynyl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an alkynyl group having1 or more substituents, for instance from 1 to 5 substituents, andparticularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Alkanoyl” or “acyl” as used herein refers to the group R²⁷—C(O)—, whereR²⁷ is hydrogen or alkyl as defined above.

“Aryl” refers to a monovalent aromatic hydrocarbon group derived by theremoval of one hydrogen atom from a single carbon atom of a parentaromatic ring system. Typical aryl groups include, but are not limitedto, groups derived from aceanthrylene, acenaphthylene,acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene,fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene,s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene,ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene,phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene,rubicene, triphenylene, trinaphthalene and the like. Particularly, anaryl group comprises from 6 to 14 carbon atoms.

“Substituted Aryl” includes those groups recited in the definition of“substituted” herein, and particularly refers to an aryl group that mayoptionally be substituted with 1 or more substituents, for instance from1 to 5 substituents, particularly 1 to 3 substituents, selected from thegroup consisting of acyl, acylamino, acyloxy, alkenyl, substitutedalkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substitutedalkyl, alkynyl, substituted alkynyl, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl ring or with an aliphatic ring.

“Alkaryl” refers to an aryl group, as defined above, substituted withone or more alkyl groups, as defined above.

“Aralkyl” or “arylalkyl” refers to an alkyl group, as defined above,substituted with one or more aryl groups, as defined above.

“Aryloxy” refers to —O-aryl groups wherein “aryl” is as defined above.

“Alkylamino” refers to the group alkyl-NR²⁸R²⁹, wherein each of R²⁸ andR²⁹ are independently selected from hydrogen and alkyl.

“Acylamino” refers to the group aryl-NR³⁰R³¹, wherein each of R³⁰ andR³¹ are independently selected from hydrogen, aryl and heteroaryl.

“Alkoxyamino” refers to a radical —N(H)OR³² where R³² represents analkyl or cycloalkyl group as defined herein.

“Alkoxycarbonyl” refers to a radical —C(O)-alkoxy where alkoxy is asdefined herein.

“Alkylarylamino” refers to a radical —NR³³R³⁴ where R³³ represents analkyl or cycloalkyl group and R³⁴ is an aryl as defined herein.

“Alkylsulfonyl” refers to a radical —S(O)₂R³⁵ where R³⁵ is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfonyl, ethylsulfonyl, propylsulfonyl,butylsulfonyl and the like.

“Alkylsulfinyl” refers to a radical —S(O)R³⁵ where R³⁵ is an alkyl orcycloalkyl group as defined herein. Representative examples include, butare not limited to, methylsulfinyl, ethylsulfinyl, propylsulfinyl,butylsulfinyl and the like.

“Alkylthio” refers to a radical —SR³⁵ where R³⁵ is an alkyl orcycloalkyl group as defined herein that may be optionally substituted asdefined herein. Representative examples include, but are not limited to,methylthio, ethylthio, propylthio, butylthio, and the like.

“Amino” refers to the radical —NH₂.

“Substituted amino” includes those groups recited in the definition of“substituted” herein, and particularly refers to the group —N(R³⁶)₂where each R³⁶ is independently selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, cycloalkyl, substituted cycloalkyl,and where both R groups are joined to form an alkylene group. When bothR groups are hydrogen, —N(R³⁶)₂ is an amino group.

“Aminocarbonyl” refers to the group —C(O)NR³⁷R³⁷ where each R³⁷ isindependently hydrogen, alkyl, aryl and cycloalkyl, or where the R³⁷groups are joined to form an alkylene group.

“Aminocarbonylamino” refers to the group —NR³⁸C(O)NR³⁸R³⁸ where each R³⁸is independently hydrogen, alkyl, aryl or cycloalkyl, or where two Rgroups are joined to form an alkylene group.

“Aminocarbonyloxy” refers to the group —OC(O)NR³⁹R³⁹ where each R³⁹ isindependently hydrogen, alkyl, aryl or cycloalky, or where the R groupsare joined to form an alkylene group.

“Arylalkyloxy” refers to an —O-arylalkyl radical where arylalkyl is asdefined herein.

“Acylamino” means a radical —NHR⁴⁰ where R⁴⁰ represents an aryl group asdefined herein.

“Aryloxycarbonyl” refers to a radical —C(O)—O-aryl where aryl is asdefined herein.

“Arylsulfonyl” refers to a radical —S(O)₂R⁴¹ where R⁴¹ is an aryl orheteroaryl group as defined herein.

“Azido” refers to the radical —N₃.

“Bicycloaryl” refers to a monovalent aromatic hydrocarbon group derivedby the removal of one hydrogen atom from a single carbon atom of aparent bicycloaromatic ring system. Typical bicycloaryl groups include,but are not limited to, groups derived from indane, indene, naphthalene,tetrahydronaphthalene, and the like. Particularly, an aryl groupcomprises from 8 to 11 carbon atoms.

“Bicycloheteroaryl” refers to a monovalent bicycloheteroaromatic groupderived by the removal of one hydrogen atom from a single atom of aparent bicycloheteroaromatic ring system. Typical bicycloheteroarylgroups include, but are not limited to, groups derived from benzofuran,benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline,phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene,isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole,naphthyridine, benzoxadiazole, pteridine, purine, benzopyran,benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine,quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline,and the like. Preferably, the bicycloheteroaryl group is between 9-11membered bicycloheteroaryl, with 5-10 membered heteroaryl beingparticularly preferred. Particular bicycloheteroaryl groups are thosederived from benzothiophene, benzofuran, benzothiazole, indole,quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.

“Carbamoyl” refers to the radical —C(O)N(R⁴²)₂ where each R⁴² group isindependently hydrogen, alkyl, cycloalkyl or aryl, as defined herein,which may be optionally substituted as defined herein.

“Carboxy” refers to the radical —C(O)OH.

“Carboxyamino” refers to the radical —N(H)C(O)OH.

“Cycloalkyl” refers to cyclic hydrocarbyl groups having from 3 to about10 carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems, which optionally can besubstituted with from 1 to 3 alkyl groups. Such cycloalkyl groupsinclude, by way of example, single ring structures such as cyclopropyl,cyclobutyl, cyclopentyl, cyclooctyl, 1-methylcyclopropyl,2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ringstructures such as adamantanyl, and the like.

“Substituted cycloalkyl” includes those groups recited in the definitionof “substituted” herein, and particularly refers to a cycloalkyl grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Cycloalkoxy” refers to the group —OR⁴³ where R⁴³ is cycloalkyl. Suchcycloalkoxy groups include, by way of example, cyclopentoxy, cyclohexoxyand the like.

“Cycloalkenyl” refers to cyclic hydrocarbyl groups having from 3 to 10carbon atoms and having a single cyclic ring or multiple condensedrings, including fused and bridged ring systems and having at least oneand particularly from 1 to 2 sites of olefinic unsaturation. Suchcycloalkenyl groups include, by way of example, single ring structuressuch as cyclohexenyl, cyclopentenyl, cyclopropenyl, and the like.

“Substituted cycloalkenyl” includes those groups recited in thedefinition of “substituted” herein, and particularly refers to acycloalkenyl group having 1 or more substituents, for instance from 1 to5 substituents, and particularly from 1 to 3 substituents, selected fromthe group consisting of acyl, acylamino, acyloxy, alkoxy, substitutedalkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Fused Cycloalkenyl” refers to a cycloalkenyl having two of its ringcarbon atoms in common with a second aliphatic or aromatic ring andhaving its olefinic unsaturation located to impart aromaticity to thecycloalkenyl ring.

“Cyanato” refers to the radical —OCN.

“Cyano” refers to the radical —CN.

“Dialkylamino” means a radical —NR⁴⁴R⁴⁵ where R⁴⁴ and R⁴⁵ independentlyrepresent an alkyl, substituted alkyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substitutedcycloheteroalkyl, heteroaryl, or substituted heteroaryl group as definedherein.

“Ethenyl” refers to substituted or unsubstituted —(C═C)—.

“Ethylene” refers to substituted or unsubstituted —(C—C)—.

“Ethynyl” refers to —(C≡C)—.

“Halo” or “halogen” refers to fluoro, chloro, bromo and iodo. Preferredhalo groups are either fluoro or chloro.

“Hydroxy” refers to the radical —OH.

“Nitro” refers to the radical —NO₂.

“Substituted” refers to a group in which one or more hydrogen atoms areeach independently replaced with the same or different substituent(s).Typical substituents include, but are not limited to, —X, —R⁴⁶, —O⁻, ═O,—OR⁴⁶, —SR⁴⁶, —S⁻, ═S, —NR⁴⁶R⁴⁷, ═NR⁴⁶, —CX₃, —CF₃, —CN, —OCN, —SCN,—NO, —NO₂, ═N₂, —N₃, —S(O)₂O⁻, —S(O)₂OH, —S(O)₂R⁴⁶, —OS(O₂)O⁻,—OS(O)₂R⁴⁶, —P(O)(O⁻)₂, —P(O)(OR⁴⁶)(O⁻), —OP(O)(OR⁴⁶)(OR⁴⁷), —C(O)R⁴⁶,—C(S)R⁴⁶, —C(O)OR⁴⁶, —C(O)NR⁴⁶R⁴⁷, —C(O)O⁻, —C(S)OR⁴⁶, —NR⁴⁸C(O)NR⁴⁶R⁴⁷,—NR⁴⁸C(S)NR⁴⁶R⁴⁷, —NR⁴⁹C(NR⁴⁸)NR⁴⁶R⁴⁷ and —C(NR⁴⁸)NR⁴⁶R⁴⁷, where each Xis independently a halogen; each R⁴⁶, R⁴⁷, R⁴⁸ and R⁴⁹ are independentlyhydrogen, alkyl, substituted alkyl, aryl, substituted alkyl, arylalkyl,substituted alkyl, cycloalkyl, substituted alkyl, cycloheteroalkyl,substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl,heteroaryl, substituted heteroaryl, heteroarylalkyl, substitutedheteroarylalkyl, —NR⁵⁰R⁵¹, —C(O)R⁵⁰ or —S(O)₂R⁵⁰ or optionally R⁵⁰ andR⁵¹ together with the atom to which they are both attached form acycloheteroalkyl or substituted cycloheteroalkyl ring; and R⁵⁰ and R⁵¹are independently hydrogen, alkyl, substituted alkyl, aryl, substitutedalkyl, arylalkyl, substituted alkyl, cycloalkyl, substituted alkyl,cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substitutedheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl orsubstituted heteroarylalkyl.

Examples of representative substituted aryls include the following

In these formulae one of R⁵² and R⁵³ may be hydrogen and at least one ofR⁵² and R⁵³ is each independently selected from alkyl, alkenyl, alkynyl,cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alkylamino,arylamino, heteroarylamino, NR⁵⁴COR⁵⁵, NR⁵⁴SOR⁵⁵,NR⁵⁴SO₂R⁵⁷, COOalkyl,COOaryl, CONR⁵⁴R⁵⁵, CONR⁵⁴OR⁵⁵, NR⁵⁴R⁵⁵, SO₂NR⁵⁴R⁵⁵, S-alkyl, S-alkyl,SOalkyl, SO₂alkyl, Saryl, SOaryl, SO₂aryl; or R⁵² and R⁵³ may be joinedto form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms,optionally containing one or more heteroatoms selected from the group N,O or S. R⁵⁴, R⁵⁵, and R⁵⁶ are independently hydrogen, alkyl, alkenyl,alkynyl, perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, substitutedaryl, heteroaryl, substituted or hetero alkyl or the like.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g.heteroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having from 1to 5, and especially from 1 to 3 heteroatoms.

“Heteroaryl” refers to a monovalent heteroaromatic group derived by theremoval of one hydrogen atom from a single atom of a parentheteroaromatic ring system. Typical heteroaryl groups include, but arenot limited to, groups derived from acridine, arsindole, carbazole,β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole,indole, indoline, indolizine, isobenzofuran, isochromene, isoindole,isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine,oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline,phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline,quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole,thiophene, triazole, xanthene, and the like. Preferably, the heteroarylgroup is between 5-15 membered heteroaryl, with 5-10 membered heteroarylbeing particularly preferred. Particular heteroaryl groups are thosederived from thiophene, pyrrole, benzothiophene, benzofuran, indole,pyridine, quinoline, imidazole, oxazole and pyrazine.

Examples of representative heteroaryls include the following:

wherein each Y is selected from carbonyl, N, NR⁵⁸, O, and S; and R⁵⁸ isindependently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl,heteroaryl, heteroalkyl or the like.

As used herein, the term “cycloheteroalkyl” refers to a stableheterocyclic non-aromatic ring and fused rings containing one or moreheteroatoms independently selected from N, O and S. A fused heterocyclicring system may include carbocyclic rings and need only include oneheterocyclic ring. Examples of heterocyclic rings include, but are notlimited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl,and are shown in the following illustrative examples:

wherein each X is selected from CR⁵⁸, CR⁵⁸ ₂, NR⁵⁸, O and S; and each Yis selected from NR⁵⁸, O and S; and R⁵⁸ is independently hydrogen,alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl orthe like. These cycloheteroalkyl rings may be optionally substitutedwith one or more groups selected from the group consisting of acyl,acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl,alkoxycarbonylamino, amino, substituted amino, aminocarbonyl,aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl,cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto,nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol,alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—. Substitutinggroups include carbonyl or thiocarbonyl which provide, for example,lactam and urea derivatives.

Examples of representative cycloheteroalkenyls include the following:

wherein each X is selected from CR⁵⁸, CR⁵⁸ ₂, NR⁵⁸, O and S; and each Yis selected from carbonyl, N, NR⁵⁸, O and S; and R⁵⁸ is independentlyhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,heteroalkyl or the like.

Examples of representative aryl having hetero atoms containingsubstitution include the following:

wherein each X is selected from CR⁵⁸ ₂, NR⁵⁸, O and S; and each Y isselected from carbonyl, NR⁵⁸, O and S; and R⁵⁸ is independentlyhydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl,heteroalkyl or the like.

“Hetero substituent” refers to a halo, O, S or N atom-containingfunctionality that may be present as an R⁴ in a R⁴C group present assubstituents directly on the ring or rings of the compounds of thisinvention, or that may be present as a substituent in any “substituted”aryl and aliphatic groups present in the compounds.

Examples of hetero substituents include:

-halo,

—NO₂, —NH₂, —NHR⁵⁹, —N(R⁵⁹)₂,

—NRCOR, —NR⁵⁹SOR⁵⁹, —NR⁵⁹SO₂R⁵⁹, OH, CN,

—CO₂H,

—R⁵⁹—OH, —O—R⁵⁹, —COOR⁵⁹,

—CON(R⁵⁹)₂, —CONROR⁵⁹,

—SO₃H, —R⁵⁹—S, —SO₂N(R⁵⁹)₂,

—S(O)R⁵⁹, —S(O)₂R⁵⁹

wherein each R⁵⁹ is independently an aryl or aliphatic, optionally withsubstitution. Among hetero substituents containing R⁵⁹ groups,preference is given to those materials having aryl and alkyl R⁵⁹ groupsas defined herein. Preferred hetero substituents are those listed above.

“Dihydroxyphosphoryl” refers to the radical —PO(OH)₂.

“Substituted dihydroxyphosphoryl” includes those groups recited in thedefinition of “substituted” herein, and particularly refers to adihydroxyphosphoryl radical wherein one or both of the hydroxyl groupsare substituted. Suitable substituents are described in detail below.

“Aminohydroxyphosphoryl” refers to the radical —PO(OH)NH₂.

“Substituted aminohydroxyphosphoryl” includes those groups recited inthe definition of “substituted” herein, and particularly refers to anaminohydroxyphosphoryl wherein the amino group is substituted with oneor two substituents. Suitable substituents are described in detailbelow. In certain embodiments, the hydroxyl group can also besubstituted.

“Thioalkoxy” refers to the group —SR⁶⁰ where R⁶⁰ is alkyl.

“Substituted thioalkoxy” includes those groups recited in the definitionof “substituted” herein, and particularly refers to a thioalkoxy grouphaving 1 or more substituents, for instance from 1 to 5 substituents,and particularly from 1 to 3 substituents, selected from the groupconsisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy,alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino,aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy,azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen,hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy,thioketo, thiol, alkyl-S(O)—, aryl-S(O)—, alkyl-S(O)₂— and aryl-S(O)₂—.

“Sulfanyl” refers to the radical HS—. “Substituted sulfanyl” refers to aradical such as RS— wherein R is any substituent described herein.

“Sulfonyl” refers to the divalent radical —S(O₂)—. “Substitutedsulfonyl” refers to a radical such as R⁶¹—(O₂)S— wherein R⁶¹ is anysubstituent described herein. “Aminosulfonyl” or “Sulfonamide” refers tothe radical H₂N(O₂)S—, and “substituted aminosulfonyl” “substitutedsulfonamide” refers to a radical such as R⁶² ₂N(O₂)S— wherein each R⁶²is independently any substituent described herein.

“Sulfone” refers to the group —SO₂R⁶³. In particular embodiments, R⁶³ isselected from H, lower alkyl, alkyl, aryl and heteroaryl.

“Thioaryloxy” refers to the group —SR⁶⁴ where R⁶⁴ is aryl.

“Thioketo” refers to the group ═S.

“Thiol” refers to the group —SH.

One having ordinary skill in the art of organic synthesis will recognizethat the maximum number of heteroatoms in a stable, chemically feasibleheterocyclic ring, whether it is aromatic or non aromatic, is determinedby the size of the ring, the degree of unsaturation and the valence ofthe heteroatoms. In general, a heterocyclic ring may have one to fourheteroatoms so long as the heteroaromatic ring is chemically feasibleand stable.

As used herein, “mammal” refers to any member of the higher vertebrateanimals comprising the class Mammalia, which includes, but is notlimited to, humans.

As used herein, an “amount effective” shall mean an amount sufficient tocover the region of skin, hair, fur, or wool surface where a change inpigmentation is desired.

“Pharmaceutically acceptable” means approved by a regulatory agency ofthe Federal or a state government or listed in the U.S. Pharmacopoeia orother generally recognized pharmacopoeia for use in animals, and moreparticularly in humans.

“Pharmaceutically acceptable salt” refers to a salt of a compound of theinvention that is pharmaceutically acceptable and/or that possesses thedesired pharmacological activity of the parent compound. Such saltsinclude: (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, N-methylglucamine and thelike. Salts further include, by way of example only, sodium, potassium,calcium, magnesium, ammonium, tetraalkylammonium, and the like; and whenthe compound contains a basic functionality, salts of non toxic organicor inorganic acids, such as hydrochloride, hydrobromide, tartrate,mesylate, acetate, maleate, oxalate and the like.

The term “pharmaceutically acceptable cation” refers to a non toxic,acceptable cationic counter-ion of an acidic functional group. Suchcations are exemplified by sodium, potassium, calcium, magnesium,ammonium, tetraalkylammonium cations, and the like.

“Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant,excipient or carrier with which a compound of the invention isadministered.

“Preventing” or “prevention” refers to a reduction in risk of acquiringa disease or disorder (i.e., causing at least one of the clinicalsymptoms of the disease not to develop in a subject not yet exposed toor predisposed to the disease, and not yet experiencing or displayingsymptoms of the disease).

“Prodrugs” refers to compounds, including derivatives of the compoundsof the invention, which have cleavable groups and become by solvolysisor under physiological conditions the compounds of the invention whichare pharmaceutically active in vivo. Such examples include, but are notlimited to, choline ester derivatives and the like, N-alkylmorpholineesters and the like.

“Solvate” refers to forms of the compound that are associated with asolvent, usually by a solvolysis reaction. Conventional solvents includewater, ethanol, acetic acid and the like. The compounds of the inventionmay be prepared e.g. in crystalline form and may be solvated orhydrated. Suitable solvates include pharmaceutically acceptablesolvates, such as hydrates, and further include both stoichiometricsolvates and non-stoichiometric solvates.

“Subject” includes humans. The terms “human,” “patient” and “subject”are used interchangeably herein.

“Therapeutically effective amount” means the amount of a compound that,when administered to a subject for treating a disease or a condition, issufficient to effect such treatment for the disease or condition. The“therapeutically effective amount” can vary depending on the compound,the disease or condition and its severity, and the age, weight, etc., ofthe subject to be treated.

“Treating” or “treatment” of any disease or disorder refers, in oneembodiment, to ameliorating the disease or disorder (i.e., arresting orreducing the development of the disease or at least one of the clinicalsymptoms thereof). In another embodiment “treating” or “treatment”refers to ameliorating at least one physical parameter, which may not bediscernible by the subject. In yet another embodiment, “treating” or“treatment” refers to modulating the disease or disorder, eitherphysically, (e.g., stabilization of a discernible symptom),physiologically, (e.g., stabilization of a physical parameter), or both.In yet another embodiment, “treating” or “treatment” refers to delayingthe onset of the disease or disorder, or even preventing the same. In astill further embodiment, “treating” or “treatment” refers toadministration of the compound or composition of the invention forcosmetic purposes.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but in the acid sensitiveform often offers advantages of solubility, tissue compatibility, ordelayed release in the mammalian organism (see, Bundgard, H., Design ofProdrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well know to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound witha substituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Preferred are the C₁ to C₈ alkyl,C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkylesters of the compounds of the invention.

As used herein, the term “isotopic variant” refers to a compound thatcontains unnatural proportions of isotopes at one or more of the atomsthat constitute such compound. For example, an “isotopic variant” of acompound can contain one or more non-radioactive isotopes, such as forexample, deuterium (²H or D), carbon-13 (¹³C), nitrogen-15 (¹⁵N), or thelike. It will be understood that, in a compound where such isotopicsubstitution is made, the following atoms, where present, may vary, sothat for example, any hydrogen may be ²H/D, any carbon may be ¹³C, orany nitrogen may be ¹⁵N, and that the presence and placement of suchatoms may be determined within the skill of the art. Likewise, theinvention may include the preparation of isotopic variants withradioisotopes, in the instance for example, where the resultingcompounds may be used for drug and/or substrate tissue distributionstudies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e.¹⁴C, are particularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Further, compounds may beprepared that are substituted with positron emitting isotopes, such as¹¹C, ¹⁸F, ¹⁵O and ¹³N, and would be useful in Positron EmissionTopography (PET) studies for examining substrate receptor occupancy.

All isotopic variants of the compounds provided herein, radioactive ornot, are intended to be encompassed within the scope of the invention.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers”. Isomersthat differ in the arrangement of their atoms in space are termed“stereoisomers”.

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of n electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenylnitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers andmixtures, racemic or otherwise, thereof. The methods for thedetermination of stereochemistry and the separation of stereoisomers arewell-known in the art.

L-Cystine Stones and L-Cystine Crystalization

L-cystine stones are aggregates of individual crystals with hexagonalhabits (FIG. 1). L-cystine can be crystallized in vitro at physiologicalpH (6≤pH≤8) by slow evaporation (a), acidification of basic L-cystinesolutions to neutral pH (l), or gradual cooling of solutionssupersaturated with L-cystine (α). Under these conditions, L-cystinecrystallizes as hexagonal plates (FIG. 1B) with large (001) basalsurfaces that can achieve widths of 400 μm and are bounded by sixequivalent {100} faces. The typical thickness of these crystals rangesfrom 10-30 μm. The crystal structure (hexagonal P6₁22 space group,a=b=0.5422 nm, c=5.6275 nm) reveals L-cystine molecules organized as ahelix about the 6₁ screw axis such that six cystine molecules span the˜5.6 nm unit cell length of the c-axis (a). The L-cystine moleculesexhibit intermolecular NH₃ ⁺ . . . ⁻O(C═O) hydrogen bonding along the 6₁screw axis (FIG. 1C, I), intermolecular S . . . S interactions betweenthe helices at intervals of c/2 along each of the six equivalent {100}directions (FIG. 2C, II), and NH₃ ⁺ . . . ⁻O(C═O) hydrogen bonding (FIG.1D, III, IV) between adjacent helices in the (001) plane. The hexagonalplate habit reflects the multiple strong intermolecular interactions inthe (001) plane. The basal surfaces of L-cystine grown at neutral pH aredecorated with {100} steps that are observable by either optical (FIG.1B) or scanning electron microscopy, as described in Rimer, et al.,Crystal Growth Inhibitors for the Prevention of L-Cystine Kidney StonesThrough Molecular Design, Science 330, 337 (2010), expresslyincorporated herein by reference in its entirety.

Crystal growth near equilibrium is commonly described by theterrace-ledge-kink model (c), wherein steps created by dislocationsadvance across crystal terraces by the addition of solute molecules tokink sites along the ledge (a ledge is the intersection of a step andterrace). Steps originating from screw dislocations typically exhibit aspiral growth pattern with the first turn occurring once each step hasreached its critical length (c). Real-time in situ AFM of the L-cystine(001) face during growth in aqueous solutions containing L-cystinerevealed steps emanating from screw dislocations, generating hexagonalhillocks in a spiral growth pattern. Occasionally, multiple dislocationswere observed (FIG. 2A,B), merging to generate a range of step heightsfrom 1 nm to 60 nm, with the larger steps observed distant from thedislocation cores where step bunching would be expected. In contrast,hillocks generated by single isolated dislocations were bounded by sixwell-defined major {100} steps, each with a ˜6 nm height correspondingto the unit cell length along c, separating (001) terraces. Each hillockterrace was decorated with six minor {100} steps at sixty degreeintervals, each with a ˜1 nm height corresponding to a single L-cystinemolecule, creating the appearance of a pinwheel. These minor steps mostlikely reflect a splitting of the dislocation into six equivalentdislocations described by a Burgers vector having a magnitude of c/6.Consecutive images during crystal growth revealed a clockwise rotationof the pinwheel at the dislocation core (i.e. a left-handed screw)accompanied by continuous generation of new hillocks. Attachment ofL-cystine molecules to both the minor and major steps on the surroundingterraces results in outward advancement of the steps with respect to thedislocation core (FIG. 2C). Notably, the spiral growth pattern also isobserved for D-cystine, the unnatural enantiomer, but withcounterclockwise (i.e. a right-handed screw) rotation of the pinwheel(FIG. 2D). A preference for screw dislocations of opposite handednessfor enantiomeric crystals has been predicted (a).

The Compounds

As described herein, the present invention relates to the prevention ofL-cystine kidney stones based on crystal growth inhibition via thebinding of tailored growth inhibitors to specific crystal surfacesthrough molecular recognition. The compounds of the invention can beused to inhibit the rate of crystal growth, reduce crystal yield, andsignificantly alter crystal habit from hexagonal platelets to needles,suggesting a new strategy for the prevention of cystinuria.

Thus, one aspect of the invention provides a method for preventinginhibiting, or slowing the growth of L-cystine crystallizationcomprising administering an effective amount of a compound of formula I:R^(1a)—[O]_(v)-(-A-L-)_(m)-A-[O]_(v)R^(1b)   I

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof; andwherein

each A is independently

each X and Y is independently S, S(O), S(O)₂, or C(R⁵)q;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(3c), R^(3d), R^(4a), R^(4b) andR⁵ is independently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,and substituted or unsubstituted cycloalkyl; the subscript q is 1 or 2;the dotted bond is a single or a double bond;provided that when one of X and Y is S, S(O), or S(O)₂, then the dottedbond is a single bond;

L is —O—C₁-C₆ alkylene-O—, —O-aryl-O—, or a group —O—(CH₂—CH₂—O—)_(t)—;the subscript t is 1-10; the subscript m is 0-10;

each R^(1a) and R^(1b) is independently selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl, and substituted or unsubstituted cycloalkyl; andeach subscript v is 0 or 1.

In one particular embodiment, with respect to formula I, when A is Ia′,both X and Y are S, S(O), or S(O)₂, and m is 0, then each subscript v is0.

In one particular aspect of the invention provides a method forpreventing inhibiting, or slowing the growth of L-cystinecrystallization comprising administering an effective amount of acompound of formula I or a pharmaceutically acceptable salt, solvate,cocrystal, or prodrug thereof, and stereoisomers, tautomers and isotopicvariants thereof; and the formula I is as described above, provided thatwhen A is Ia′, both X and Y are S, S(O), or S(O)₂, and m is 0, then eachsubscript v is 0.

In one embodiment, the present invention excludes compounds according toformula I, wherein A is Ia′, both X and Y are S, S(O), or S(O)₂, m is 0,each subscript v is 1, and each R^(1a) and R^(1b) is independently H,Me, Et, i-Pr or t-Bu.

In one particular embodiment, with respect to formula I, when A is Ia′,both X and Y are S, S(O), or S(O)₂, and m is 0, each subscript v is 1;then at least one of R^(1a) and R^(1b) is substituted or unsubstitutedPh. One particular embodiment, each of R^(1a) and R^(1b) is substitutedor unsubstituted Ph. One particular embodiment, each of R^(1a) andR^(1b) is unsubstituted Ph.

In one embodiment, with respect to formula I, A is

and wherein each R^(2a), R^(2b), R^(3a), R^(3b), R^(3c), R^(3d), R^(4a),R^(4b) and R⁵ are as described for formula I.

In one embodiment, with respect to formula I, the subscript m is 1-5.

In one embodiment, with respect to formula I, L is —O—CH₂—O—. In anotherembodiment L is —O—CH₂—CH₂—O—.

In one embodiment, with respect to formula I, L is

In one embodiment, with respect to formula I, L is —O—(CH₂—CH₂—O)_(t)—;and the subscript t is 1; In another embodiment the subscript t is 2.

In one embodiment, with respect to formula I, subscript m is 0; and thesubscript v is O.

In one embodiment, with respect to formula I, subscript m is 0; and thecompound is according to formula II:R^(1a)-A-R^(1b)   II;

and wherein A, R^(1a) and R^(1b) are as described for formula I.

Another aspect of the invention provides a method for preventing,inhibiting or slowing the growth of L-cystine crystallization comprisingadministering an effective amount of a compound of formulae IIIa, IIIb,IIIc, IIId, or IIIe:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof; andwherein

each R^(1a) and R^(1b) is independently selected from H, substituted orunsubstituted alkyl, substituted or unsubstituted aryl, substituted orunsubstituted aralkyl, and substituted or unsubstituted cycloalkyl;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(3c), R^(3d), R^(4a), R^(4b) andR⁵ is independently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,and substituted or unsubstituted cycloalkyl; and the subscript v is 0,1, or 2.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIe, each each R^(2a), R^(2b), R^(3a), R^(3b), R^(3c), R^(3d),R^(4a), R^(4b) and R⁵ is independently H or alkyl.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIe, each of R^(4a) and R^(4b) is H.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, one of R^(4a) and R^(4b) is H; and the other is alkyl.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIc, one of R^(4a) and R^(4b) is H; and the other is Me, Et,i-Pr, n-Pr, or n-Bu.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, each of R^(4a) and R^(4b) is alkyl.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, each of R^(4a) and R^(4b) is Me, Et, i-Pr, n-Pr, or n-Bu.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, each of R^(4a) and R^(4b) is Me.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, one of R⁵ is H; and the other is Me, Et, i-Pr, n-Pr, orn-Bu.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, each R⁵ is alkyl.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, each R⁵ is H.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIe, Rob, and R⁵ is independently selected from H, and alkyl.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIe, each of R^(2a) and R^(2b) is H.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, one of R^(2a) and R^(2b) is H; and the other is alkyl.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, one of R^(2a) and R^(2b) is H; and the other isindependently Me, Et, i-Pr, n-Pr, or n-Bu.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, each of R^(2a) and R^(2b) is alkyl.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, each of R^(2a) and R^(2b) is independently Me, Et, i-Pr,n-Pr, or n-Bu.

In one particular embodiment of the invention, with respect to formulaI, II, or IIIa-IIIe, each of R^(2a) and R^(2b) is Me.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIe, each of R^(3c) and R^(3d) is H.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, one of R^(3c) and R^(3d) is H; and the other is alkyl.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, one of R^(3c) and R^(3d) is H; and the other isindependently Me, Et, i-Pr, n-Pr, or n-Bu.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, each of R^(3c) and R^(3d) is alkyl.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, each of R^(3c) and R^(3d) is independently Me, Et, i-Pr,n-Pr, or n-Bu.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIe, each of R^(3c) and R^(3d) is Me.

Another aspect of the invention provides a method for preventing,inhibiting or slowing the growth of L-cystine crystallization comprisingadministering an effective amount of a compound of formulae IIIf, orIIIg:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof; andwherein

each R^(1a) and R^(1b) is independently selected from H, alkyl, alkenyl,alkynyl, aryl, aralkyl, and cycloalkyl;

each R^(2a), R^(2b), R^(3a), R^(3b), R^(3c), R^(3d), and R^(4a) isindependently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,and substituted or unsubstituted cycloalkyl; and the subscript v is 0,1, or 2.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIg, R^(2a), each R^(2a), R^(2b), R^(3a), R^(3b), R^(3c), R^(3d),and R^(4a) is independently selected from H, and alkyl.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIg, R^(4a) is H.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIg, R^(4a) is alkyl.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIg, R^(4a) is Me, Et, i-Pr, n-Pr, or n-Bu.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIg, R^(2a) is H.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIg, R^(2a) is alkyl.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIg, R^(2a) is Me, Et, i-Pr, n-Pr, or n-Bu.

In one embodiment of the invention, with respect to formula I, II, orIIIa-IIIg, each of R^(3a) and R^(3b) is H.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIg, one of R^(3a) and R^(3b) is H; and the other is alkyl.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIg, one of R^(3a) and R^(3b) is H; and the other isindependently Me, Et, i-Pr, n-Pr, or n-Bu.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIg, each of R^(3a) and R^(3b) is alkyl.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIg, each of R^(3a) and R^(3b) is independently Me, Et, i-Pr,n-Pr, or n-Bu.

In another embodiment of the invention, with respect to formula I, II,or IIIa-IIIg, each of R^(3a) and R^(3b) is Me.

In one embodiment of the invention, with respect to formula I, thecompound is according to formula IVa, IVb, IVc or IVd:

and wherein R^(1a) and R^(1b) are as with respect to formula I; or apharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one embodiment of the invention, with respect to formula I, thecompound is according to formula IVe, or IVf:

and wherein R^(1a) and R^(1b) are as with respect to formula I; or apharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one particular embodiment of the invention, with respect to formulaI, the compound is according to formula Va, Vb, Vc, or Vd:

and wherein R^(1a) and R^(1b) are as with respect to formula I; or apharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one embodiment of the invention, with respect to formula I, thecompound is according to formula VIa, VIb, VIc, or VId:

and wherein R^(1a) and R^(1b) are as with respect to formula I; or apharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one particular embodiment of the invention, with respect to formulaI, the compound is according to formula VIIa, VIIb, VIIc, or VIId:

and wherein R^(1a) and R^(1b) are as with respect to formula I; or apharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one embodiment of the invention, with respect to formula I-VIId, oneof R^(1a) and R^(1b) is H; and the other is alkyl.

In another embodiment of the invention, with respect to formula I-VIId,one of R^(1a) and R^(1b) is H; and the other is independently Me, Et,n-Pr, i-Pr, n-Bu, or t-Bu.

In another embodiment of the invention, with respect to formula I-VIId,one of R^(1a) and R^(1b) is H; and the other is alkenyl.

T In another embodiment of the invention, with respect to formulaI-VIId, one of R^(1a) and R^(1b) is H; and the other is alkynyl.

In another embodiment of the invention, with respect to formula I-VIId,one of R^(1a) and R^(1b) is H; and the other is propargyl.

In another embodiment of the invention, with respect to formula I-VIId,one of R^(1a) and R^(1b) is H; and the other is cycloalkyl.

In another embodiment of the invention, with respect to formula I-VIId,one of R^(1a) and R^(1b) is H; and the other is cyclohexyl, cyclopentyl,cyclobutyl, or cyclopropyl.

In another embodiment of the invention, with respect to formula I-VIId,one of R^(1a) and R^(1b) is H; and the other is Me, Et, or cyclopropyl.

In another embodiment of the invention, with respect to formula I-VIId,each of R^(1a) and R^(1b) is alkyl.

In another embodiment of the invention, with respect to formula I-VIId,each of R^(1a) and R^(1b) is independently Me, Et, n-Pr, i-Pr, n-Bu, ort-Bu.

In another embodiment of the invention, with respect to formula I-VIId,each of R^(1a) and R^(1b) is alkenyl.

In another embodiment of the invention, with respect to formula I-VIId,each of R^(1a) and R^(1b) is alkynyl.

In another embodiment of the invention, with respect to formula I-VIId,each of R^(1a) and R^(1b) is propargyl.

In another embodiment of the invention, with respect to formula I-VIId,each of R^(1a) and R^(1b) is cycloalkyl.

In another embodiment of the invention, with respect to formula I-VIId,each of R^(1a) and R^(1b) is independently cyclohexyl, cyclopentyl,cyclobutyl, or cyclopropyl.

In another embodiment of the invention, with respect to formula I-VIId,each of R^(1a) and R^(1b) is independently Me, Et, or cyclopropyl.

In one particular embodiment of the invention, with respect to formulaI-VIId, each of R^(1a) and R^(1b) is Me.

In one particular embodiment of the invention, with respect to formulaI-VIId, each of R^(1a) and R^(1b) is substituted or unsubstituted Ph.

Another aspect of the invention provides a method for preventing,inhibiting or slowing the growth of L-cystine crystallization comprisingadministering an effective amount of cystamine.

In one embodiment of the invention, with respect to formula I, thecompound is according to formula VIIIa or VIIIb:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one embodiment of the invention, with respect to formula I, thecompound is according to formula formula IXa, or IXb:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one particular embodiment of the invention, with respect to formulaI, the compound is according to formula Xa or Xb:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one particular embodiment of the invention, with respect to formulaI, the compound is according to formula XI:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one particular embodiment of the invention, with respect to formulaI, the compound is according to formula XIIa, XIIb, XIIc, or XIId:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one embodiment of the invention, with respect to formula XIIa-XIId,R^(1a) is substituted or unsubstituted alkyl, substituted orunsubstituted aryl, substituted or unsubstituted aralkyl, or substitutedor unsubstituted cycloalkyl.

In one embodiment of the invention, with respect to formula XIIa-XIId,R^(1a) is alkenyl.

In one embodiment of the invention, with respect to formula XIIa-XIId,R^(1a) is alkynyl.

In one embodiment of the invention, with respect to formula XIIa-XIId,R^(1a) is propargyl.

In one embodiment of the invention, with respect to formula XIIa-XIId,R^(1a) is cycloalkyl.

In one embodiment of the invention, with respect to formula XIIa-XIId,R^(1a) is cyclohexyl, cyclopentyl, cyclobutyl, or cyclopropyl.

In one embodiment of the invention, with respect to formula XIIa-XIId,R^(1a) is Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, or Ph.

In one embodiment of the invention, with respect to formula XIIa-XIId,R^(1a) is substituted or unsubstituted Ph.

In one particular embodiment of the invention, with respect to formulaI, the compound is according to formula XIIIa, XIIIb, XIIIc, or XIIId:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one particular embodiment of the invention, with respect to formulaI, the compound is according to formula XIVa, XIVb, XIVc, or XIVd:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one particular embodiment of the invention, with respect to formulaI, the compound is according to formula XVa, XVb, XVc, or XVd:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one embodiment of the invention, with respect to formula I, thecompound is according to formula XVI:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one embodiment of the invention, with respect to formula I, thecompound is according to formula XVII:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof.

In one particular embodiment of the invention, with respect to formulaXVa-XVd, XVI, and XVII, Ph is unstituted. In another embodiment Ph issubstituted. In a particular embodiment, Ph is substituted with alkyl,haloalkyl, alkoxy, or halo.

In one particular embodiment of the invention, with respect to formulaI, the compound is any one of the compounds listed in Table 1.

In one particular embodiment of the invention, with respect to formulaI, the compound is any one of the compounds listed in Table 1, andwherein the compound # is 2, 3, 9, 10, 12, or 14.

In one particular embodiment of the invention, with respect to formulaI, the compound is any one of the compounds listed in Table 1, andwherein the compound # is 2.

In one particular embodiment of the invention, with respect to formulaI, the compound is L-cysteine methyl ester.

In one particular embodiment of the invention, with respect to formulaI, the compound is L-homocystine dimethyl ester.

In one particular embodiment of the invention, with respect to formulaI, the compound is L-dimethyl 2,7-diamino oct-4-enedioate.

In one particular embodiment of the invention, with respect to formulaI, the compound is L-dimethyl 2,7-diamino octanedioate.

In one particular embodiment of the invention, with respect to formulaI, the compound is N-acetyl-L-cysteine methyl ester.

In one particular embodiment of the invention, with respect to formulaI, the compound is L-diaminooctanedioic acid.

In one particular embodiment of the invention, with respect to formulaI, N-acetyl-L-cysteine.

In one particular embodiment of the invention, with respect to formulaI, the compound is L-serine methyl ester.

In one particular embodiment of the invention, with respect to formulaI, the compound is L-cystine diphenyl ester.

Another aspect of the invention provides a pharmaceutical compositionfor preventing, inhibiting, or slowing the growth of L-cystinecrystallization comprising a pharmaceutically acceptable carrier and apharmaceutically effective amount of a compound according to formula I,II, IIIa-IIIg, IVa-IVd, Va-Vd, VIa-VId, VIIa-VIId, VIIIa-VIIIb, IXa-IXd,Xa-Xb, XI, XIIa-XIId, XIIIa-XIIId, XIVa-XIVd, XVa-XVd, XVI or XVII.

Yet another aspect of the invention provides a method for preventing,inhibiting or slowing growth of L-cystine kidney-stone formation in asubject in need thereof, the method comprising administering to thesubject a pharmaceutically effective amount of a compound according toformula I, II, IIIa-IIIg, IVa-IVd, Va-Vd, VIa-VId, VIIa-VIId,VIIIa-VIIIb, IXa-IXd, Xa-Xb, XI, XIIa-XIId, XIIIa-XIIId, XIVa-XIVd,XVa-XVd, XVI or XVII.

Yet another aspect of the invention provides a method of treating asubject having chronic kidney disease, comprising administering to thesubject a pharmaceutically effective amount of a compound according toformula I, II, IIIa-IIIg, IVa-IVd, Va-Vd, VIa-VId, VIIa-VIId,VIIIa-VIIIb, IXa-IXd, Xa-Xb, XI, XIIa-XIId, XIIIa-XIIId, XIVa-XIVd,XVa-XVd, XVI or XVII.

In one embodiment, with respect to the above methods, the subject ishuman.

A further aspect of the invention provides a method for reducing aL-cystine crystal concentration in a human or animal comprisingadministering to a human or animal a pharmaceutically effective amountof a compound according to formula I, II, IIIa-IIIg, IVa-IVd, Va-Vd,VIa-VId, VIIa-VIId, VIIIa-VIIIb, IXa-IXd, Xa-Xb, XI, XIIa-XIId,XIIIa-XIIId, XIVa-XIVd, XVa-XVd, XVI or XVII.

A further aspect of the invention provides a method for treating aL-cystine crystal related condition in a human or animal comprisingadministering to a human or animal a pharmaceutically effective amountof a compound according to formula I, II, IIIa-IIIg, IVa-IVd, Va-Vd,VIa-VId, VIIa-VIId, VIIIa-VIIIb, IXa-IXd, Xa-Xb, XI, XIIa-XIId,XIIIa-XIIId, XIVa-XIVd, XVa-XVd, XVI or XVII.

A further aspect of the invention provides a combination to treat orprevent an L-cystine crystal-related condition consisting of a compoundaccording to formula I, II, IIIa-IIIg, IVa-IVd, Va-Vd, VIa-VId,VIIa-VIId, VIIIa-VIIIb, IXa-IXd, Xa-Xb, XI, XIIa-XIId, XIIIa-XIIId,XIVa-XIVd, XVa-XVd, XVI or XVII, and another treatment or treatments,which may include high fluid intake or alkalinizing potassium or sodiumsalts.

In one embodiment, with respect to the above methods, the L-cystinerelated condition is cystinuria.

In one embodiment, with respect to the above methods, the L-cystinerelated condition is kidney stone disease.

In certain aspects, the present invention provides prodrugs andderivatives of the compounds of the invention. Prodrugs are derivativesof the compounds of the invention, which have metabolically cleavablegroups and become by solvolysis or under physiological conditions thecompounds of the invention, which are pharmaceutically active, in vivo.Such examples include, but are not limited to, choline ester derivativesand the like, N-alkylmorpholine esters and the like.

Other derivatives of the compounds of this invention have activity inboth their acid and acid derivative forms, but the acid sensitive formoften offers advantages of solubility, tissue compatibility, or delayedrelease in the mammalian organism (see, Bundgard, H., Design ofProdrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs includeacid derivatives well know to practitioners of the art, such as, forexample, esters prepared by reaction of the parent acid with a suitablealcohol, or amides prepared by reaction of the parent acid compound witha substituted or unsubstituted amine, or acid anhydrides, or mixedanhydrides. Simple aliphatic or aromatic esters, amides and anhydridesderived from acidic groups pendant on the compounds of this inventionare preferred prodrugs. In some cases it is desirable to prepare doubleester type prodrugs such as (acyloxy)alkyl esters or((alkoxycarbonyl)oxy)alkylesters. Preferred are the C₁ to C₈ alkyl,C₂-C₈ alkenyl, aryl, C₇-C₁₂ substituted aryl, and C₇-C₁₂ arylalkylesters of the compounds of the invention.

The present invention also relates to the pharmaceutically acceptableacid addition and base salts of any of the aforementioned compounds ofinvention. The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the aforementioned base compounds ofthis invention are those which form non-toxic acid addition salts, ie.,salts containing pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, acetate, lactate, citrate, acid citrate,tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate and pamoate (i.e.,1,1-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

The compounds useful according to the invention that are basic in natureare capable of forming a wide variety of different salts with variousinorganic and organic acids. Although such salts must bepharmaceutically acceptable for administration to animals, it is oftendesirable in practice to initially isolate a compound of formula I fromthe reaction mixture as a pharmaceutically unacceptable salt and thensimply convert the latter back to the free base compound by treatmentwith an alkaline reagent and subsequently convert the latter free baseto a pharmaceutically acceptable acid addition salt. The acid additionsalts of the active base compounds of this invention are readilyprepared by treating the base compound with a substantially equivalentamount of the chosen mineral or organic acid in an aqueous solventmedium or in a suitable organic solvent, such as methanol or ethanol.Upon careful evaporation of the solvent, the desired solid salt isreadily obtained.

Those compounds useful according to the invention that are acidic innature are capable of forming base salts with various pharmaceuticallyacceptable cations. Examples of such salts include the alkali metal andalkaline earth metal salts and, particularly, the sodium and potassiumsalts. These salts can be prepared by conventional techniques. Thechemical bases that are used as reagents to prepare the pharmaceuticallyacceptable base salts of this invention are those that form non-toxicbase salts with the acidic compounds of formula I. Such non-toxic basesalts include those derived from such pharmaceutically acceptablecations as sodium, potassium, calcium and magnesium, etc. These saltscan easily be prepared by treating the corresponding acidic compoundswith an aqueous solution containing the desired pharmaceuticallyacceptable cations, and then evaporating the resulting solution todryness, preferably under reduced pressure. Alternatively, they can alsobe prepared by mixing lower alkanolic solutions of the acidic compoundsand the desired alkali metal alkoxide together, and then evaporating theresulting solution to dryness, as described above. In either case,stoichiometric quantities of reagents are preferably employed in orderto ensure completeness of reaction and maximum yields of the desiredfinal products.

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the invention,preferred methods and materials are described below. The materials,methods, and examples are illustrative only and not intended to belimiting. Other features and advantages of the invention will beapparent from the detailed description, examples, and the claims.

Pharmaceutical Applications

For pharmaceutical uses, it is preferred that the compounds of theinvention are part of a pharmaceutical composition. Pharmaceuticalcompositions, comprising an effective amount of such a compound in apharmaceutically acceptable carrier, can be administered to a patient,person, or animal having a disease, disorder, or condition as describedherein.

The amount of compound which will be effective in the treatment of aparticular disease, disorder, or condition will depend on the nature ofthe disease, disorder, or condition, and can be determined by standardclinical techniques. Where possible, it is desirable to determine invitro the cytotoxicity of the compound to the tissue type to be treated,and then in a useful animal model system prior to testing and use inhumans.

The compounds can be administered by any conventional means availablefor use in conjunction with pharmaceuticals, either as individualtherapeutic agents or in a combination of therapeutic agents. Each canbe administered alone, but is preferably administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice. The pharmaceuticalcompositions of the invention can be adapted for oral, and parenteraladministration, and can be in unit dosage form, in a manner well knownto those skilled in the pharmaceutical art. Parenteral administrationincludes but is not limited to, injection subcutaneously, intravenously,intraperitoneally or intramuscularly. Oral application is preferred,however.

For oral administration, gelatin capsules or liquid-filled soft gelatincapsules can contain the active ingredient and powdered or liquidcarriers, such as lactose, lecithin starch, cellulose derivatives,magnesium stearate, stearic acid, and the like. Similar diluents can beused to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar-coated or film-coated to mask any unpleasant taste and to protectthe tablet from the atmosphere, or enteric-coated for selective,targeted disintegration in the gastrointestinal tract. Liquid dosageforms for oral administration can contain coloring and/or flavoring toincrease patient acceptance.

In general, sterile water, oil, saline, aqueous dextrose (glucose),polysorbate and related sugar solutions and glycols such as propyleneglycol or polyethylene glycols, are suitable carriers for parenteralsolutions. Solutions or emulsions for parenteral administrationpreferably contain about 5-15% polysorbate 80 or lecithin, suitablestabilizing agents and, if necessary, buffer substances. Antioxidizingagents such as, but not limited to, sodium bisulfate, sodium sulfite, orascorbic acid, either alone or combined, are suitable stabilizingagents. Also useful are citric acid and its salts, and sodium EDTA. Inaddition, parenteral solutions can contain preservatives including, butnot limited to, benzalkonium chloride, methyl- or propyl-paraben, andchlorobutanol.

As will be understood by those in the art, the compositions andpharmaceutical compositions of the invention may be provided in the formof a kit. Kits of the invention comprise one or more specificcompositions and/or pharmaceutical compositions of the invention.Optionally, the kit further contains printed instructions as a label orpackage insert directing the use of such reagents to modify skinpigmentation, i.e., to lighten skin as appropriate to the particularincluded composition. These compounds are provided in a containerdesigned to prevent contamination, minimize evaporation or drying of thecomposition, etc. The compounds may or may not be provided in a presetunit dose or usage amount.

General Methods of Preparation

The compounds of this invention can be purchased from commercial sourcesand tested for their activities. The test compounds which are notcommercially available can be prepared from readily available startingmaterials using various general methods and procedures known in the art.For example, the compounds may be synthetically prepared from knownstarting materials by conventional laboratory procedures and protocols.Likewise, those compounds that may be found in existing naturalmaterials may be isolated and/or purified by known procedures, to attainthe requisite concentration and content of the active, to be efficaciouswhen formulated into compositions in accordance with the presentinvention. Such preparations may also be described as formulations ormaterials that are enriched for the particular compound(s) of theinvention, and the present invention embraces such preparations withinits scope.

Additionally, as will be apparent to those skilled in the art withrespect to the methods of preparation of the compounds of the inventioninvolving organic synthesis, conventional protecting groups may benecessary to prevent certain functional groups from undergoing undesiredreactions. The choice of a suitable protecting group for a particularfunctional group as well as suitable conditions for protection anddeprotection are well known in the art. For example, numerous protectinggroups, and their introduction and removal, are described in T. W.Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, SecondEdition, Wiley, New York, 1991, and references cited therein.

Materials:

L-cystine (99%), cystamine dihydrochloride (98%), L-cystinedimethylester dihydrochloride (≥95%) (CDME),N-(2-Mercaptopropionyl)glycine (Thiola), N_(α),N_(α)′-di-Boc-L-cystine(cystine-boc), N-acetyl-L-cysteine methyl ester (ALCME),N-acetyl-L-cysteine (ALC), cystamine, L-Homocystine, L-serine methylester (SME), poly(acrylic acid) partial sodium salt (50 wt % in H₂O, 5kDa), poly-L-aspartic acid sodium salt (12.3 kDa), poly-L-glutamic acidsodium salt (13.6 kDa), poly-L-lysine hydrobromide (15 kDa),poly-L-arginine hydrochloride (14 kDa), apo-transferrin (human, >98%),chondroitin (sulfate A sodium salt from bovine trachea), human serumalbumin (fatty-acid free, 99%), sodium citrate (dihydrate),S-tert-butylmercapto-L-cysteine, D-penicillamine disulfide, and3,3′-dithiodipropionic acid (99%), L-cysteine (>97%), and L-cysteinemethyl ester hydrochloride (98%) (HCME) were obtained from Sigma Aldrichand used without purification. Osteopontin, extracted and purified frombovine milk, was donated by Esben Sorenson (University of Aarhus,Denmark) and contains 7 wt % Ca²⁺ ions (as determined with ionchromatography). Tamm-Horsfall protein (THP) was obtained from a humansample with no personal or family history of kidney stone disease. THPwas isolated and purified using previously reported procedures, and aportion of the native protein was desialylated by treatment with theenzyme neuraminidase (resulting in a 50% reduction of carbohydratecontent). Type I and type III antifreeze proteins (AFPs) purified fromcold ocean teleost fish were used as received from A/F Protein, Inc.(Waltham, Mass.). All solutions were prepared using deionized water(18.2 MΩ) purified with a Direct-Q 3 Millipore purification system.

Synthesis of Intermediates

The following compounds may be used as intermediates to synthesize thecompounds of the invention.

Boc protected L-cystine methyl ester (CME)

Synthetic Scheme:

Synthesis of Cystine Dimethyl Ester Dihydrochloride (CDME)

A stream of dry hydrogen chloride gas was sparged rapidly into asuspension of cystine (10 g) in anhydrous methanol (50 mL) and agitatedwith a magnetic stirrer. After all the cystine had dissolved the warmsolution was cooled in an ice bath, and sparging of HCl continued tosaturation at 0-5° C. The reaction mixture was protected fromatmospheric moisture with a calcium chloride drying tube and allowed tostand at room temperature for 3 hours. Solvent was removed from thereaction mixture under reduced pressure on a o rotary evaporator withthe water bath set at 50° C. An aliquot of methanol (50 mL) was added tothe resulting syrup and then concentration by rotary evaporationrepeated. To the dry syrupy residue was added anhydrous ether (20 mL)resulting in spontaneous crystallization. The mixture was allowed tostand overnight at 4° C. and the resulting crystalline suspension wascollected by filtration in a buchner funnel and washed with coldanhydrous ether (30 mL). The filter cake was dried under reducedpressure over potassium hydroxide pellets in a desiccator.

Synthesis of CDME-Boc

Et₃N (2.6 g, 17.6 mmol) was slowly added to a stirred solution of CDME(1.5 g, 4.4 mmol, Compound 2) in CH₂Cl₂ (20 mL) at 0° C. After stirringfor 10 min, di-tert-butyl dicarbonate (T-Boc, 2.2 g, 10.12 mmol) inCH₂Cl₂ (20 mL) was added dropwise over the course of approximately 2hours. The reaction was stirred overnight and allowed to slowly warm toroom temperature. The mixture was extracted with CH₂Cl₂ (2×200 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography on silica gel(hexane/AcOEt=11/7) to yield the compound CDME-Boc. ¹HNMR (400 MHz,CDCl₃): δ=5.4 (br, 2H), 4.6 (br, 2H), 3.8 (s, 6H) 1.45 (s, 18H). ¹HNMRspectra of CDME-Boc exhibit a ratio of 3:1 for the H peak of Boc tomethyl ester.

Reduction of CDME-Boc to CME-Boc

To a stirred solution of CDME-Boc (0.5 g, 1.1 mmol) in methanol (20 mL)was slowly added NaOH (0.054 g, 1.3 mmol) in water (20 mL) forapproximately 2 hours at 0° C. After stirring the solution overnight andallowed it to reach room temperature, 0.5 M HCl was added to achieve apH 1.0 solution. The mixture was extracted with CH₂Cl₂ (2×200 mL). Thecombined organic layers were dried over Na₂SO₄ and concentrated invacuo. The residue was purified by column chromatography on silica gel(MeOH/CH₂Cl₂=1/10) to yield CME-Boc. ¹HNMR (400 MHz, CDCl₃): δ=5.8 (br,2H), 4.5 (br, 2H), 3.8 (s, 3H) 1.45 (s, 18H). ¹HNMR spectra of theCME-Boc exhibit a ratio of 6:1 for the H peak of Boc to methyl ester.

Synthesis of Compounds of the Invention Synthesis of Oligomer Compoundsof the Invention

The oligomer compounds can be prepared by following the followingsynthetic scheme.

Synthesis of C—C Compounds of the Invention

The C—C analogs of cystine compounds may be prepared by followingliterature methods. A representative synthetic scheme which can be usedto prepare the C—C compounds of the invention is given below, which isdescribed in Synthetic Communications (2006), 36(12), 1707-1713.

Step 1: Synthesis of L-allylglycine methyl ester (AGME)

Dissolve L-allyglycine salt (1.85 g) in 24 mL CH₃OH, add 2 mL thionylchloride. The mixture was stirred overnight and allowed to slowly warmto room temperature. The residue was concentrated in vacuo. ¹HNMR (400MHz, CDCl₃): δ=5.87 (m, 1H), 5.31 (m, 2H), 4.25 (br, 1H), 3.81 (s, 1H),2.86 (br, 2H).

Step 2: Synthesis of L-AGME-Boc

Et₃N (2.7 g) was slowly added to a stirred solution of L-AGME (2 g) inCH₂Cl₂ (20 mL) at 0° C. After stirring for 10 min, di-tert-butyldicarbonate (T-Boc, 3.6 g) in CH₂Cl₂ (20 mL) was added dropwise. Thereaction was stirred overnight and allowed to slowly warm to roomtemperature. The mixture was extracted with CH₂Cl₂ (2×200 mL). Thecombined organic layers were dried over MgSO₄ and concentrated in vacuo.¹HNMR (400 MHz, CDCl₃): δ=5.70 (m, 1H), 5.15 (m, 2H), 5.05 (br, 1H),4.38 (m, 1H), 3.72 (s, 3H), 2.48 (m, 2H), 1.44 (s, 9H).

Step 3: Synthesis of Dimethyl (2S,7S)-Bis-(tert-butoxycarbonyl)amino-4-octenedioate (AGME-Boc dimer)

A solution of L-AGME-Boc (200 mg) in CH₂Cl₂ (6 mL) was evacuated andthen bubbled with N₂ for 5 min, and then add the Grubbs II catalyst (58mg) in CH₂Cl₂ (1 mL). The solution was refluxed overnight. And then theresidue was concentrated in vacuo. The residue was purified by columnchromatography on silica gel (Hexane/EtOAc=8/2) to yield the compoundL-AGME-Boc dimer. ¹HNMR (400 MHz, CDCl₃): δ=5.42 (bs, 2H), 5.13 (br,2H), 4.35 (m, 2H), 3.75 (s, 6H), 2.47 (m, 4H), 1.45 (s, 18H).

Step 4: Synthesis of Dimethyl(2S,7S)-bis-(tert-butoxycarbonyl)aminooctanedioate (AGME-Boc-single)

Dissolve L-AGME-Boc dimer (80 mg) in ethyl acetate (20 mL), and then add10% Pd/C (40 mg) in the solution, the solution was flushed with H₂ 3times. The mixture was filled with H₂ and shaked over night. The mixturewas purified after a short column of silica gel to get rid of Pd/C. Theresidue was concentrated in vacuo. ¹HNMR (400 MHz, CDCl₃): δ=5.05 (br,2H), 4.27 (br, 2H), 3.73 (s, 6H), 1.76 (m, 2H), 1.61 (m, 2H), 1.43 (s,18H), 1.36 (m, 4H).

Step 5: Synthesis of(2S,7S)-2,7-bis((tert-butoxycarbonyl)amino)octanedioic acid (AG-Bocacid)

Dissolve L-AGME-Boc-single (0.40 g) in 10 mL CH₃OH, then prepare NaOHsolution (0.12 g in 20 mL H₂O), add the NaOH solution into methanolsolution, and then reflux overnight. Evaporate the methanol using vacuumevaporation, and then achieve the ion exchange using 36 (wet)ion-exchange resin during 30 mins.

Step 6: Synthesis of (1S,6S)-1,6-dicarboxyhexane-1,6-diaminium chloride(CCacid)

Add 20 mL HCl in EA (1M) into the AG-Boc acid, stir for overnight. Thenevaporate to get rid of extra ethyl acetate. The mixture was extractedwith CH₂Cl₂ (2×200 mL). Evaporate the H₂O away, get the pure solid.

¹HNMR (400 MHz, MeOD₄): 6=4.02 (tr, 1H), 1.98 (m, 2H), 1.60 (m, 2H)

Synthesis of S—C Compounds of the Invention

The S—C analogs of cystine compounds may be prepared by followingliterature methods. A representative synthetic scheme which can be usedto prepare the S—C compounds of the invention is given below:

Synthesis of C═C Compounds of the Invention

The C═C analogs of cystine compounds may be prepared by followingliterature methods. A representative synthetic scheme which can be usedto prepare the C═C compounds of the invention is given below:

Synthesis of S—S Acyl Compounds of the Invention

The S—S analogs of acyl cystine compounds may be prepared by followingliterature methods. A representative synthetic scheme which can be usedto prepare the S—S acyl compounds of the invention is given below:

Synthetic Methods to Prepare Cystine Sulfoxides and Sulfone Derivatives

The cystine sulfoxides and sulfone derivatives may be prepared byfollowing synthetic methods described in Tetrahedron Letters, 45(50),9237-9240; 2004; or in Journal of Organic Chemistry, 50(22), 4332-6;1985.

Additional General methods for sulfoxides and sulfones may be found inTetrahedron Letters (2004), 45(50), 9237-9240.

General Synthetic Methods to Prepare N-Alkyl Cystine s Derivatives

The N-alkyl derivatives may be prepared by following synthetic methodsdescribed in Indian Journal of Chemistry, Section B: Organic ChemistryIncluding Medicinal Chemistry, 37B(1), 10-14; 1998; Heterocycles, 67(2),519-522; 2006; or in Indian Journal of Chemistry, Section B: OrganicChemistry Including Medicinal Chemistry, 37B(1), 10-14; 1998

Additional methods to prepared compounds of the invention may be foundin: Facile synthesis of β-amino disulfides, cystines, and their directincorporation into peptides. Nasir, Baig R. B.; Kanimozhi, Catherine K.;Sudhir, V. Sai; Chandrasekaran, Srinivasan. Department of OrganicChemistry, Indian Institute of Science, Bangalore, India. Synlett(2009), (8), 1227-1232; and

Conversion of thiosulfinate derivatives of cystine to unsymmetricalcystines and lanthionines by reaction with tris(dialkylamino)phosphines.Olsen, Richard K.; Kini, Ganesh D.; Hennen, William J. Dep. Chem.Biochem., Utah State Univ., Logan, Utah, USA. Journal of OrganicChemistry (1985), 50(22), 4332-6. CODEN: JOCEAH ISSN: 0022-3263. Journalwritten in English.

The synthesis of representative compounds of the invention is givenbelow.

Example 1 Synthesis of L-cystine diethyl ester dihydrochloride

Step 1: Synthesis of L-CDEE-Boc

CH₂Cl₂ (20 mL) and ethanol (1.5 mL) were added to the L-cys-Boc (2.0 g)and DMAP (0.1 g), after stirring for 10 min, DCC (2.8 g) was added intothe solution during 30 min. The reaction was stirred overnight andallowed to slowly warm to room temperature. The solution was filteredand the filtrate was concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel (hexane/EtOAc=7/3) to yield thecompound L-CDEE-Boc. ¹HNMR (400 MHz, CDCl₃): δ=5.39 (br, 1H), 4.46 (br,1H), 4.05 (br, 2H), 1.45 (s, 9H), 1.20 (br, 3H). ¹HNMR spectra wererecorded using a Bruker AVANCE 400 spectrometer using broadbanddecoupling.

Step 2: Removal of Boc from L-CDEE-Boc

70 ml 1.25M HCl/Ethanol was added to L-CDEE-Boc (1.5 g) and the mixturewas stirred overnight. The mixture was then extracted with H₂O (2×200mL), L-CDEE was obtained as the hydrochloride salt after lyophilization.The salt was crystallized from ethanol/ethyl acetate to give the pureL-CDEE. ¹HNMR (400 MHz, D₂O): 6=4.38 (br, 2H), 4.23 (br, 2H), 3.33 (br,2H), 1.272 (s, 6H).

Example 2 Synthesis of L-cystine isopropyl ester (L-CDIE)

The compound was prepared following the procedure used to prepare CDEE.For CDIE preparation ethanol was replaced with isopropanol.

L-CDIE-Boc: ¹HNMR (400 MHz, CDCl₃): δ=5.42 (br, 1H), 5.07 (br, 1H), 4.56(br, 1H), 3.17 (br, 2H), 1.45 (s, 9H), 1.16 (br, 6H).L-CDIE salt: ¹HNMR(400 MHz, D₂O): 6=5.08 (br, 1H), 4.45 (br, 1H), 3.30 (br, 2H), 1.250 (s,6H).

Example 3 Synthesis of L-cystine di-tert-butyl ester (L-CDTE)

Synthesis of L-cystine di-tert-butyl ester perchlorate (CDTE)

L-Cystine (10.0 g, 42 mmol) is dissolved in perchloric acid (70% aq.v/v, 16.6 mL) and treated slowly with 100 mL tert-butyl acetate. Afterstirring the mixture for overnight, a white solid is separated. Themixture is cooled on ice for 30 min and the solid is collected byfiltration, washed with cold ethyl ether and dried to yield the puresolid of L-CDTE perchlorate. L-CDTE perchlorate: ¹HNMR (400 MHz, CD₃OD):δ=4.35 (br, 1H), 3.40 (m, 1H), 3.25 (m, 2H), 1.56 (s, 9H).

Example 4 Synthesis of L-homocystine dimethyl ester dihydrochloride(HOMOME)

Step 1: Synthesis of L-homocystine-Boc

L-homocystine (0.50 g) was dissolved in 20 mL 1,4-dioxane and treatedwith NaOH solution (0.313 g in 20 mL H₂O). The mixture was stirred for10 min. and then treated with di-tert-butyl carbonate (1.02 g). Thereaction was stirred overnight and was allowed to warm to roomtemperature slowly. 10 mL HCl (1M) was then added into the mixture toadjust pH to 1, and the mixture was extracted using ethyl acetate. Theorganic layer was separated and the solvent was removed to give thecrude homocystine-boc, as a white solid.

Step 2: Synthesis of L-homocystine dimethyl ester-Boc (L-homome-boc)

CH₂Cl₂ (20 mL) and methanol (2 mL) were added to the L-homocystine-Boc(0.80 g) and DMAP (0.1 g). After stirring for 10 min, DCC (1.05 g) wasadded into the solution over a period of 30 min. The reaction wasstirred overnight and allowed to warm to room temperature slowly. Thesolution was filtered and the filtrate was concentrated in vacuo. Theresidue was purified by column chromatography on silica gel(hexane/EtOAc=7/3) to yield the compound L-homome-Boc. ¹HNMR (400 MHz,CDCl₃): δ=5.10 (br, 1H), 4.42 (br, 1H), 3.72 (s, 3H), 2.72 (br, 2H),2.25 (br, 1H), 2.05 (br, 1H), 1.45 (s, 9H).

Step 3: Removal of Boc from L-homome-Boc

20 ml 1.25M HCl/ethyl acetate was added to L-homome-Boc (0.5 g) and themixture was stirred overnight. The mixture was then extracted with H₂O(2×200 mL). Homome was obtained as the hydrochloride salt afterlyophilization. ¹HNMR (400 MHz, CD₃OD): δ=4.24 (br, 2H), 4.10 (br, 2H),3.91 (s, 3H), 2.81 (br, 2H), 2.48 (br, 2H).

Crystallization of L-Cystine Preparation of Hexagonal L-Cystine Crystals

Syntheses of L-cystine reported in the literature vary in approach,often employing acidic solutions (pH<1) that generate three crystallinestructures: L-cystine dihydrochloride, L-cystine dihydrochloridedihydrate, and L-cystine (hexagonal). A reported protocol forrecrystallization of L-cystine in 0.5% HCl was followed [S1], whichyielded largest crystals with (0001) surfaces void of observable steps,as confirmed by AFM topographical imaging that revealed roughenedsurfaces without terraces. This protocol was modified by using solutionsat physiological pH (i.e. pH˜7), which generated hexagonal crystals withmultiple, terraced steps that were visible even by optical microscopy.Hexagonal L-cystine crystal platelets were synthesized for AFMmeasurements of surface topography and real time in situ growth. Asupersaturated L-cystine solution was prepared by adding 70 mg ofL-cystine to a 250 mL round-bottom flask containing 100 mL of deionizedwater. A heating mantle was pre-heated for 10 min, and then thesupersaturated L-cystine solution was refluxed at 100° C. for 20 minwith stirring to completely dissolve L-cystine. The boiling solution wasgradually cooled on the heating mantel while continuously condensing andstirring for 75 min. The solution was then transferred into a 100 mLbeaker, sealed to prevent evaporation and exposure to airborneparticulates, and stored overnight at room temperature without stirring.Single crystals were collected by vacuum filtration (Whatman Grade 1filters, >11 μm pores) and were air dried prior to analysis.

Alternatively, the hexagonal crystals can be obtained by crystallizationperformed near neutral pH (Sa) The hexagonal form was crystallized froma supersaturated L-cystine solution prepared by adding 70 mg ofL-cystine to 100 mL of deionized water (3 mM), and heating under refluxat 100° C. for 20 min with stirring to completely dissolve L-cystine.The resulting solution corresponds to a relative supersaturation ofσ˜7.5, based on the lower bound of reported solubility (0.4-0.7 mM at pH7, 25° C.) (Sb, Sc, Sd). This concentration was used for bulkcrystallization studies in the presence of additives so that ameasurable amount of bulk crystals could be obtained in a reasonabletime. The solution was then allowed to cool slowly with stirring for 75min. 30 mL aliquots were transferred to separate glass containers, whichwere then sealed to prevent evaporation and exposure to airborneparticulates and stored for 72 hours at room temperature withoutstirring. Single crystals were collected by vacuum filtration (WhatmanGrade 1 filters, >11 μm pores) and were air dried prior to analysis. Thecrystals retrieved in this manner were used for AFM studies by mountingindividual crystals according to the procedure described below.

Bulk Crystallization in the Presence of Compounds of the Invention(Additive).

The compounds of the present invention may be prepared and tested fortheir crystal growth inhibition properties using the proceduresdescribed herein. For example, the aforementioned procedure forhexagonal platelet crystallization is repeated. Following the 75 mincooling period, prior to any observable crystallization, a compound ofthe invention is added to the supersaturated L-cystine solution to thedesired concentration. The container is sealed and stored for 72 hoursat room temperature without stirring, after which the precipitate iscollected by vacuum filtration (Whatman Grade 1 filters, >11 μm pores)and is air dried prior to analysis. Crystallization without additive isperformed in an identical manner for comparison using a control solutionfrom the same batch. The mass yields of L-cystine crystals are obtainedby dividing the mass of L-cystine crystals (collected from growthsolution by filtration) by the mass of L-cystine added in the growthsolution. The crystals are isolated with 11 μm-pore filters, which areregarded as sufficiently small for reliable capture of the crystals(optical micrographs reveal that the size of crystals is always greaterthan 50 μm.

Materials Characterization

An Orion 3 Star pH meter (Thermo Electron Corp.) with Orion 9157BNMDprobe is used to measure the pH of L-cystine solutions. Crystalmorphology is measured with a Leitz ERGOLUZ optical microscope and aHitachi 3500 scanning electron microscopy. A thin coating of gold (2 nm)is sputtered on SEM samples and images are acquired at low voltage (2-5kV) to minimize sample melting. ¹H NMR spectra are recorded using aBruker AVANCE 400 spectrometer and are routinely run using broadbanddecoupling. Chemical shifts (δ), expressed in ppm, are referenced to thecorresponding residual nuclei in deuterated solvent (D₂O). Powder X-raydiffraction (XRD) patterns of isolated crystals are acquired with aPanalytical XPert PRO MPD using a Bragg-Brentano geometry with fixedslits at power settings of 45 kV and 40 mA. A CuKα radiation (0.154 nm)source is used with a 1 degree fixed divergence slit (10 mm beam mask)for incident X-rays and a 1 degree anti-scatter slit Ni filter (1/16degree peceiving slit) for diffracted X-rays.

Single Crystal X-Ray Diffraction (SCXRD):

Patterns are acquired with a Bruker SMART ApexII CCD area detector on aD8 goniometer. The tεmperature during the data collection is controlledwith an Oxford Cryosystems Series 700 plus instrument. Preliminarylattice parameters and orientation matrices are obtained from three setsof frames. Data are collected using graphite-monochromated and 0.5mm-MonoCap-collimated Mo—K_(α) radiation (λ=0.71073 Å) with the co scanmethod (Bruker APEXII). Data are processed with the SAINT+ program forreduction and cell refinement. Multi-scan absorption corrections areapplied by using the SADABS program for area detector. The structure issolved by the direct method (SHELXS-97) and refined on F² (SHELXL-97)(G. M. Sheldrick, Universität Göttingen, Germany).

AFM Characterization:

A Digital Instruments (Santa Barbara, Calif.) Nanoscope IIIa Multimodesystem is used for topographical and lattice imaging. All measurementsare performed in contact mode using Veeco NP—B Si₃N₄ cantilever tipswith a spring constant of 0.12 N/m (triangular, 196 μm length, 41 μmwidth) on a glass cantilever holder, and a liquid cell is created for insitu step velocity measurements. All L-cystine crystals for AFMmeasurements are prepared by the method described herein. Crystals aretransferred onto an AFM specimen disk coated with partially cured (1 hr)UV-curable optical cement (Type SK-9, EMS Acquisition Corp.) by gentlypressing the disk against hexagonal platelets or L-cystine needlesisolated by filtration (Whatman Nuclepore membrane, 8 μm). The (0001)face of hexagonal platelets is exposed normal to the disk for AFManalysis with growth occurring along equivalent {1010} faces in thelateral directions, while the sides of L-cystine needles are exposednormal to the disc. The partially cured polymer with adhered crystals iscompletely cured by additional UV radiation (2 hrs) prior to analysis.Measurements of individual step heights for hexagonal L-cystine crystalsare acquired in air (contact mode) at a scan rate of 1.00 Hz and 256samples per line over a 15×15 μm² surface area. Integral andproportional gains are set to the highest possible values withoutobtaining feedback. Four hexagonal crystals (5 areas per crystal) areanalyzed for statistical step height distributions, which are calculatedfrom >10³ individual steps. Lattice-resolved images of crystal surfacesare acquired in water (contact mode) using a scan rate of 112 Hz over a12×12 nm² area.

In Situ AFM Growth Measurements:

Real time in situ step velocity measurements of L-cystine growth areassessed along six structurally-equivalent {1010} faces of the hexagonalstructure. A liquid cell is created with the glass cantilever tipholder, and working solutions are injected through a 1-mL syringe. Priorto injecting the growth medium (i.e. supersaturated L-cystine solution),crystals are etched with deionized water in the fluid cell for one hourto remove amorphous deposits or impurities that may be present on thesurface. Supersaturated solutions (0.5 g/L) are generated by addingL-cystine to deionized water, boiling the solution on a heating mantlefor 20 min to completely dissolve the solute, and allowing the solutionto cool for 20 min on the heating mantle before transferring thesolution (via syringe) to the AFM fluid cell. This method allows thesolution to gradually cool to room temperature prior to AFM measurementsin an effort to minimize premature nucleation of L-cystine in the growthsolution.

The effect of the compound of invention (additives) on crystal growthrates is investigated. Additives are combined with the supersaturatedL-cystine following the 20 min cool down period (as discussed above) toavoid denaturing biological additives at higher temperature. A smallvolume (0.2 mL) of concentrated additive is mixed with 4.8 mL ofL-cystine to generate 0.48 g/L L-cystine solutions with additives ofvarying concentrations. Control measurements without additive areperformed in a similar manner, replacing concentrated additive solutionsdeionized water to maintain a constant L-cystine concentration. Datacollection is started immediately after injecting the working solutioninto the AFM liquid cell. For each measurement, growth is first assessedin the absence of additive, then in the presence of additive on theidentical area of the crystal surface to analyze relative changes instep velocity. Measurements are acquired at static conditions withoutrefreshment of growth solution using supersaturated L-cystine solutionssix times larger than the solubility of L-cystine in water, which isreported as 0.4-0.7 mM (pH 7, 25° C.). At these conditions, stepadvancement is observable at a reasonable timescale; however,supersaturated solutions with L-cystine concentrations three timessolubility did not result in step growth during the time of measurement.At static conditions, solute is depleted from solution during growth,leading to a slight decrease in the step velocity with increasing time.As such, the total number of crystals adhered to the sample disk areminimized to lower the total surface area of crystals exposed to thegrowth solution, thereby minimizing depletion of solute. Topographicalimages are acquired at maximal integral and proportional gains (i.e.without feedback) using a scan rate of 5.1 Hz (256 samples per line) anda scan area of 5×5 μm². Crystal growth on the (0001) surface is measuredas the distance a step advanced with time using consecutive deflectionimages where the acquisition time for each complete scan isapproximately 50 sec.

The AFM measurement data obtained for the compounds of invention istabulated in Table 1, below, wherein V_(o) is the velocity of stepadvancement in the absence of prospective inhibitors; V is the velocityof step advancement in the presence of a prospective inhibitor; V/V_(o)is the normalized velocity, that is, the ratio of the velocity in thepresence of the inhibitor to the velocity in the absence of inhibitor(lower values are tantamount to more effective inhibition); V_(o)/V isthe inverse of V/V_(o) (higher values are tantamount to more effectiveinhibition).

TABLE 1 Inhibitory Data for Compounds of Invention Concen- tration #Name Full Name Structure (mM) V/Vo Vo/V  1 CDME L-cystine dimethyl ester

0.015 0.38 2.62  2 CDPE L-cystine diphenyl ester

0.015 0.41 2.44  3 HCME L-cysteine methyl ester

0.03 0.49 2.05  4 CDEE L-cystine diethyl ester

0.015 0.56 1.79  5 HOMOME L-homocystine dimethyl ester

0.015 0.63 1.59  6 CDIE L-cystine diisopropyl ester

0.015 0.64 1.55  7 CME L-cystine methyl ester

0.015 0.68 1.47  8 CDTE L-cystine ditert-butyl ester

0.015 0.7 1.43  9 thiola N-(2- Mercapto- propionyl)glycine

0.03 0.74 1.35 10 C═CME L-dimethyl 2,7- diaminooct-4-enedioate

0.015 0.81 1.23 11 Cystine- Boc N_(α),N_(α)′-di-Boc-L-cystine

0.09 0.81 1.23 12 CCME L-dimethyl 2,7- diaminooctanedioate

0.015 0.92 1.09 13 ALCME N-acetyl-L-cysteine methyl ester

0.03 0.96 1.05 14 Ccacid L-diaminooctanedioic acid

0.015 0.97 1.03 15 ALC N-acetyl-L-cysteine

0.03 0.99 1.02 16 Cyst- amine cystamine

0.015 1 1 17 cysteine L-cysteine

0.03 1 1 18 Homo- cystine L-Homocystine

0.015 1.05 0.95 19 SME L-serine methyl ester

0.03 1.07 0.93X-Ray Diffraction

There are four reported crystal structures of L-cystine havinghexagonal, tetragonal, and monoclinic structures. Single crystal X-raydiffraction (SCXRD) measurements of L-cystine crystals yielded unit cellparameters that agree with reported structural data (Table 2). The smallsize of L-cystine tetragonal needles required a synchrotron X-ray sourceto obtain the unit cell parameters.

TABLE 2 Comparison of crystal unit cell parameters Unit Cell SpaceParameters (A) Cell Angles (deg) Volume Compound Ref Group a b c α β γ(A³) C₆H₁₄N₂O₄S₂ ²⁺ 2(Cl⁻) [S5] C2 18.6 5.3 7.2 90 103.6 90 687 OW 18.55.2 7.3 90 104.1 90 678 C₆H₁₄N₂O₄S₂ ²⁺2(Cl⁻) 2(H₂O) [S6] P2₁ 5.9 13.29.4 90 90.8 90 728 OW 5.9 13.2 9.3 90 90.6 90 717 C₆H₁₂N₂O₄S₂(Hexagonal) [S7] P6₁22 5.4 5.4 56.2 90 90 120 1433 OW 5.4 5.4 57.0 90 90120 1455 C₆H₁₂N₂O₄S₂ [S8] P4₁ 6.7 6.7 21.7 90 90 90 978 OW 6.7 6.7 21.690 90 90 971 C₈H₁₄N₂O₄S₂ ²⁺ 2(Cl⁻) [S9] P2₁ 5.9 9.3 14.8 90 91.5 90 808H₂O OW 5.9 9.1 14.9 90 91.6 90 831 [5] Steinrauf et al., [6] Kominami etal., [7] Oughton et al., [8] Chaney et al., [9] Vijayalakshmi et al.; OW= Our work

While certain of the preferred embodiments of the present invention havebeen described and specifically exemplified above, it is not intendedthat the invention be limited to such embodiments. Various modificationsmay be made thereto without departing from the scope and spirit of thepresent invention, as set forth in the following claims.

From the foregoing description, various modifications and changes in thecompositions and methods of this invention will occur to those skilledin the art. All such modifications coming within the scope of theappended claims are intended to be included therein.

All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

The chemical names of compounds given in this application were generatedusing various commercially available chemical naming software toolsincluding MDL's ISIS Draw Autonom Software tool, and were not verified.Particularly, in the event of inconsistency, the depicted structuregoverns.

REFERENCES

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What is claimed is:
 1. A method for preventing, inhibiting, or slowingthe growth of L-cystine crystallization comprising administering aneffective amount of a compound of formula I:R^(1a)—[O]_(v)-(-A-L-)_(m)-A-[O]_(v)—R^(1b)   I or a pharmaceuticallyacceptable salt, solvate, cocrystal, or prodrug thereof, andstereoisomers, tautomers and isotopic variants thereof; and wherein eachA is independently

each X and Y is independently S, S(O), S(O)₂, or C(R⁵)_(q); each R^(2a),R^(2b), R^(3a), R^(3b), R^(3c), R^(3d), R^(4a), R^(4b) and R⁵ isindependently selected from H, substituted or unsubstituted alkyl,substituted or unsubstituted aryl, substituted or unsubstituted aralkyl,and substituted or unsubstituted cycloalkyl; the subscript q is 1 or 2;the dotted bond is a single or a double bond; provided that when one ofX and Y is S, S(O), or S(O)₂, then the dotted bond is a single bond; Lis —O—C₁-C₆ alkylene-O—, —O-aryl-O—, or a group —O—(CH₂—CH₂—O—)_(t)—;the subscript t is 1-10; the subscript m is 0-10; and each R^(1a) andR^(1b) is independently selected from H, substituted or unsubstitutedalkyl, substituted or unsubstituted aryl, substituted or unsubstitutedaralkyl, and substituted or unsubstituted cycloalkyl; and each subscriptv is 0 or 1; and wherein if: 1) the compound of formula I is formulaIIIg, 2) R^(1a), R^(1b), R^(3a), and R^(3b) are all H, 3) the subscriptv of formula IIIg is 0, and 4) one of R^(2a) and R^(4a) is Me, then theother of R^(2a) and R^(4a) is not H; and wherein the compound of formulaI is not formula XIIId.
 2. The method according to claim 1 wherein thecompound is of formula I; and A is:

and wherein R^(2a), R^(2b), R^(3a), R^(3b), R^(3c), R^(3d), R^(4a),R^(4b) and R⁵ are as in claim
 1. 3. The method according to claim 1wherein the compound is of formula I; the subscript m is 0; thesubscript v is 0; and the compound is according to formula II:R^(1a)-A-R^(1b)   II; and wherein A, R^(1a) and R^(1b) are as inclaim
 1. 4. The method according to claim 1, wherein the compound is offormula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, or IIIg:

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof; andwherein each R^(1a) and R^(1b) is independently selected from H,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted aryl, substituted or unsubstituted aralkyl, andsubstituted or unsubstituted cycloalkyl; each R^(2a), R^(2b), R^(3a),R^(3b), R^(3c), R^(3d), R^(4a), R^(4b) and R⁵ is independently selectedfrom H, substituted or unsubstituted alkyl, substituted or unsubstitutedaryl, substituted or unsubstituted aralkyl, and substituted orunsubstituted cycloalkyl; and the subscript v is 0, 1, or
 2. 5. Themethod of claim 1, wherein the compound is according to formula IVa,IVb, IVc, IVd, IVe, IVf, Va, Vb, Vc, Vd, Ve, Vf, Vg, Vh, VIa, VIb, VIc,VId, VIIa, VIIb, VIIc, VIId, XIIa, XIIb, XIIc, or XIId:

and wherein R^(1a) and R^(1b) are as in claim 1; or a pharmaceuticallyacceptable salt, solvate, cocrystal, or prodrug thereof, andstereoisomers, tautomers and isotopic variants thereof.
 6. The method ofclaim 1, wherein one of R^(1a) and R^(1b) is H; and the other is alkylor aryl.
 7. The method of claim 1, wherein one of R^(1a) and R^(1b) isH; and the other is Me, Et, n-Pr, i-Pr, n-Bu, t-Bu, cyclohexyl,cyclopropyl, or Ph.
 8. The method of claim 1, wherein each of R^(1a) andR^(1b) is alkyl, cycloalkyl, or aryl.
 9. The method of claim 1, whereineach of R^(1a) and R^(1b) is independently Me, Et, n-Pr, i-Pr, n-Bu,t-Bu, or Ph.
 10. The method of claim 1, wherein each of R^(1a) andR^(1b) is alkenyl or each of R^(1a) and R^(1b) is alkynyl.
 11. Themethod of claim 1, wherein each of R^(1a) and R^(1b) is Ph.
 12. Themethod of claim 1, wherein the compound is according to formula VIIIa,VIIIb, IXa, IXb, IXc, IXd, Xa, Xb, XI, XIIIa, XIIIb, XIIIc, XIVa, XIVb,XIVc, XIVd, XVa, XVb, XVc, XVd, XVI, or XVII:

or

or a pharmaceutically acceptable salt, solvate, cocrystal, or prodrugthereof, and stereoisomers, tautomers and isotopic variants thereof. 13.The method of claim 1, wherein the compound is one of the compoundslisted in Table 1, wherein the compound # is 2, 9, 10, 12, or
 14. 14. Apharmaceutical composition for preventing, inhibiting, or slowing thegrowth of L-cystine crystallization comprising a pharmaceuticallyacceptable carrier and a pharmaceutically effective amount of a compoundas defined in claim
 1. 15. The composition of claim 14 wherein thecarrier is a parenteral carrier, oral or topical carrier.
 16. A methodfor preventing, inhibiting or slowing growth of L-cystine kidney-stoneformation in a subject in need thereof, the method comprisingadministering a pharmaceutically effective amount of a compound asdefined in claim 1 to the subject.
 17. A method of treating a subjecthaving chronic kidney disease, comprising administering apharmaceutically effective amount of a compound as defined in claim 1.18. A method for reducing a L-cystine crystal concentration in a humanor animal comprising administering to a human or animal apharmaceutically effective amount of a compound as defined in claim 1.19. A method for treating a L-cystine crystal related condition in ahuman or animal comprising administering to a human or animal apharmaceutically effective amount of a compound as defined in claim 1.20. The method or the combination according to claim 18, wherein theL-cystine related condition is cystinuria or kidney stone disease.